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WO2016160598A1 - Formes solvatées d'un inhibiteur de la tyrosine kinase de bruton - Google Patents

Formes solvatées d'un inhibiteur de la tyrosine kinase de bruton Download PDF

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Publication number
WO2016160598A1
WO2016160598A1 PCT/US2016/024305 US2016024305W WO2016160598A1 WO 2016160598 A1 WO2016160598 A1 WO 2016160598A1 US 2016024305 W US2016024305 W US 2016024305W WO 2016160598 A1 WO2016160598 A1 WO 2016160598A1
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WIPO (PCT)
Prior art keywords
theta
crystalline form
solvate
same
xrpd
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PCT/US2016/024305
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English (en)
Inventor
Erick Goldman
Mark Stephen SMYTH
Thierry Bonnaud
Alberto MUNOZ GARCIA
Christopher Peter WORRALL
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Pharmacyclics Llc
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Priority to CN201680026436.5A priority Critical patent/CN107530346A/zh
Priority to AU2016243116A priority patent/AU2016243116A1/en
Priority to BR112017020744A priority patent/BR112017020744A2/pt
Priority to JP2017550541A priority patent/JP2018509457A/ja
Application filed by Pharmacyclics Llc filed Critical Pharmacyclics Llc
Priority to MX2017012430A priority patent/MX2017012430A/es
Priority to EP16773859.0A priority patent/EP3273961A4/fr
Priority to US15/561,615 priority patent/US20180072738A1/en
Priority to CA2981048A priority patent/CA2981048A1/fr
Publication of WO2016160598A1 publication Critical patent/WO2016160598A1/fr
Priority to HK18107889.9A priority patent/HK1248147A1/zh
Priority to HK18109251.5A priority patent/HK1249737A1/zh
Priority to US16/224,565 priority patent/US20190367519A1/en
Priority to US16/697,865 priority patent/US20200347063A1/en
Priority to US17/318,148 priority patent/US20220106317A1/en
Priority to JP2021187233A priority patent/JP2022033783A/ja

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N23/00—Investigating or analysing materials by the use of wave or particle radiation, e.g. X-rays or neutrons, not covered by groups G01N3/00 – G01N17/00, G01N21/00 or G01N22/00
    • G01N23/20—Investigating or analysing materials by the use of wave or particle radiation, e.g. X-rays or neutrons, not covered by groups G01N3/00 – G01N17/00, G01N21/00 or G01N22/00 by using diffraction of the radiation by the materials, e.g. for investigating crystal structure; by using scattering of the radiation by the materials, e.g. for investigating non-crystalline materials; by using reflection of the radiation by the materials
    • G01N23/20075—Investigating or analysing materials by the use of wave or particle radiation, e.g. X-rays or neutrons, not covered by groups G01N3/00 – G01N17/00, G01N21/00 or G01N22/00 by using diffraction of the radiation by the materials, e.g. for investigating crystal structure; by using scattering of the radiation by the materials, e.g. for investigating non-crystalline materials; by using reflection of the radiation by the materials by measuring interferences of X-rays, e.g. Borrmann effect

Definitions

  • Described herein are solvates of the Bruton's tyrosine kinase (Btk) inhibitor l-((R)-3-(4- amino-3 -(4-phenoxyphenyl)- lH-pyrazolo[3 ,4-d]pyrimidin- 1 -yl)piperidin- 1 -yl)prop-2-en- 1 -one, including crystalline forms and pharmaceutically acceptable salts thereof, as
  • compositions that include the Btk inhibitor and methods of using the Btk inhibitor in the treatment of diseases or conditions that would benefit from inhibition of Btk activity.
  • Btk Bruton's tyrosine kinase
  • BCR cell surface B-cell receptor
  • Btk is a key regulator of B-cell development, activation, signaling, and survival.
  • Btk plays a role in a number of other hematopoetic cell signaling pathways, e.g., Toll like receptor (TLR) and cytokine receptor-mediated TNF-a production in macrophages, IgE receptor (FcepsilonRI) signaling in Mast cells, inhibition of Fas/APO-1 apoptotic signaling in B- lineage lymphoid cells, and collagen-stimulated platelet aggregation.
  • TLR Toll like receptor
  • FcepsilonRI IgE receptor
  • solvates of the Btk inhibitor l-((R)-3-(4-amino-3-(4- phenoxyphenyl)- lH-pyrazolo[3 ,4-d]pyrimidin- 1 -yl)piperidin- 1 -yl)prop-2-en- 1 -one including pharmaceutically acceptable polymorphs and amorphous phases, and methods of uses thereof.
  • pharmaceutically acceptable salts of the solvated Btk inhibitor including pharmaceutically acceptable polymorphs, and amorphous phases, and methods of uses thereof.
  • l-((R)-3-(4-Amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l- yl)prop-2-en-l-one are used in the manufacture of medicaments for the treatment of diseases or conditions that are associated with Btk activity.
  • l-((R)-3-(4-Amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l- yl)piperidin-l-yl)prop-2-en-l-one is an irreversible Btk inhibitor.
  • compositions that include the solvated Btk inhibitor and methods of using the solvated Btk inhibitor in the treatment of diseases or conditions (including diseases or conditions wherein irreversible inhibition of Btk provides therapeutic benefit to a mammal having the disease or condition).
  • l-((R)-3-(4-amino-3-(4-phenoxyphenyl)-lH- pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one is solvated with butyronitrile, 1,2- dimethoxyethane, hexafluorobenzene, acetophenone, chlorobenzene, dimethylacetamide, benzyl acetate, or 1,1,2-trichloroethane, or a combination thereof.
  • solvate wherein l-((R)-3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l- yl)prop-2-en-l-one is solvated with butyronitrile.
  • solvate wherein 1- ((R)-3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l-yl)prop-2- en-l-one is solvated with 1,2-dimethoxy ethane.
  • In one embodiment is a solvate, wherein 1-((R)- 3 -(4-amino-3 -(4-phenoxyphenyl)- lH-pyrazolo[3 ,4-d]pyrimidin- 1 -yl)piperidin- 1 -yl)prop-2-en- 1 - one is solvated with hexafluorobenzene.
  • solvate wherein l-((R)-3-(4- amino-3 -(4-phenoxyphenyl)- lH-pyrazolo[3 ,4-d]pyrimidin- 1 -yl)piperidin- 1 -yl)prop-2-en- 1 -one is solvated with acetophenone.
  • solvate wherein l-((R)-3-(4-amino-3-(4- phenoxyphenyl)- lH-pyrazolo[3 ,4-d]pyrimidin- 1 -yl)piperidin- 1 -yl)prop-2-en- 1 -one is solvated with chlorobenzene.
  • In one embodiment is a solvate, wherein l-((R)-3-(4-amino-3-(4- phenoxyphenyl)- lH-pyrazolo[3 ,4-d]pyrimidin- 1 -yl)piperidin- 1 -yl)prop-2-en- 1 -one is solvated with dimethylacetamide.
  • In one embodiment is a solvate, wherein l-((R)-3-(4-amino-3-(4- phenoxyphenyl)- lH-pyrazolo[3 ,4-d]pyrimidin- 1 -yl)piperidin- 1 -yl)prop-2-en- 1 -one is solvated with benzyl acetate.
  • In one embodiment is a solvate, wherein l-((R)-3-(4-amino-3-(4- phenoxyphenyl)- lH-pyrazolo[3 ,4-d]pyrimidin- 1 -yl)piperidin- 1 -yl)prop-2-en- 1 -one is solvated with 1 , 1 ,2-trichloroethane.
  • the solvate is anhydrous.
  • the solvate is crystalline.
  • the solvate is amorphous.
  • described herein is a bis-butyronitrile solvate of l-((R)-3-(4-amino-3-(4- phenoxyphenyl)- lH-pyrazolo[3 ,4-d]pyrimidin- 1 -yl)piperidin- 1 -yl)prop-2-en- 1 -one.
  • crystalline form (Form 1) of a butyronitrile solvate of l-((R)-3-(4- amino-3 -(4-phenoxyphenyl)- lH-pyrazolo[3 ,4-d]pyrimidin- 1 -yl)piperidin- 1 -yl)prop-2-en- 1 -one that has at least one of the following properties:
  • thermo-gravimetric analysis (TGA) thermogram substantially the same as the one set forth in Figure 2;
  • the crystalline form of the butyronitrile solvate of Compound 1 (Form 1) has an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 1.
  • the crystalline form of the butyronitrile solvate of Compound 1 (Form 1) has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 5.5 ⁇ 0.1° 2-Theta, 10.9 ⁇ 0.1° 2-Theta, 13.6 ⁇ 0.1° 2-Theta, 14.8 ⁇ 0.1° 2-Theta, 17.3 ⁇ 0.1° 2-Theta, 18.7 ⁇ 0.1° 2-Theta, 20.0 ⁇ 0.1° 2-Theta, and 21.8 ⁇ 0.1° 2-Theta.
  • the crystalline form of the butyronitrile solvate of Compound 1 (Form 1) has a DSC thermogram substantially the same as the one set forth in Figure 2. In some embodiments, the crystalline form of the butyronitrile solvate of Compound 1 (Form 1) has a thermo-gravimetric analysis (TGA) thermogram substantially the same as the one set forth in Figure 2. In some embodiments, the crystalline form of the butyronitrile solvate of Compound 1 (Form 1) has a DSC thermogram with an endotherm at between about 100-125°C. In some embodiments, the endotherm event have an onset at about 110 °C, a first peak at about 120 °C and a second peak at about 121 °C. In some embodiments, the DSC thermogram further has an endotherm having an onset at about 153°C and a peak at about 156°C. In some embodiments, the crystalline form of the
  • butyronitrile solvate of Compound 1 is characterized as having properties (a), (b), (c), (d), and (e). [0015] In one aspect, described herein is a hemi-dimethoxyethane of l-((R)-3-(4-amino-3-(4- phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one.
  • crystalline form of a 1,2-dimethoxy ethane solvate of 1- ((R)-3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l-yl)prop-2- en-l-one that has at least one of the following properties:
  • thermo-gravimetric analysis (TGA) thermogram substantially the same as the one set forth in Figure 4;
  • the crystalline form of the 1,2-dimethoxy ethane solvate of Compound 1 has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 3.
  • the crystalline form of the 1,2-dimethoxy ethane solvate of Compound 1 (Form 2) has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 6.8 ⁇ 0.1° 2-Theta, 13.4 ⁇ 0.1° 2-Theta, 17.6 ⁇ 0.1° 2-Theta, 18.2 ⁇ 0.1° 2- Theta, 20.2 ⁇ 0.1° 2-Theta, 21.2 ⁇ 0.1° 2-Theta, and 22.2 ⁇ 0.1° 2-Theta.
  • the crystalline form of the 1,2-dimethoxy ethane solvate of Compound 1 (Form 2) has a substantially the same X-ray powder diffraction (XRPD) pattern post storage at 40°C and 75% RH for at least a week.
  • the crystalline form of the 1,2-dimethoxy ethane solvate of Compound 1 (Form 2) has a DSC thermogram substantially the same as the one set forth in Figure 4.
  • the crystalline form of the 1,2-dimethoxy ethane solvate of Compound 1 (Form 2) has a DSC thermogram with an endotherm having an onset at about 89°C and a peak at about 101°C.
  • the crystalline form of the 1,2- dimethoxyethane solvate of Compound 1 (Form 2) has a thermo-gravimetric analysis (TGA) thermogram substantially the same as the one set forth in Figure 4.
  • TGA thermo-gravimetric analysis
  • the crystalline form of the 1,2-dimethoxy ethane solvate of Compound 1 (Form 2) is characterized as having properties (a), (b), (c), (d), (e), and (f).
  • Compound 1 (Form 3) has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 5.
  • the crystalline form of the hexafluorobenzene solvate of Compound 1 (Form 3) has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 5.4 ⁇ 0.1° 2-Theta, 14.0 ⁇ 0.1° 2-Theta, 16.1 ⁇ 0.1° 2-Theta, 18.6 ⁇ 0.1° 2- Theta, 19.3 ⁇ 0.1° 2-Theta, 22.4 ⁇ 0.1° 2-Theta, and 23.6 ⁇ 0.1° 2-Theta.
  • the crystalline form of the hexafluorobenzene solvate of Compound 1 (Form 3) has a DSC thermogram substantially the same as the one set forth in Figure 6.
  • the crystalline form of the hexafluorobenzene solvate of Compound 1 (Form 3) has a DSC thermogram with an endotherm having an onset at about 51°C. In some embodiments, the endotherm has a peak at about 75°C.
  • the crystalline form of the hexafluorobenzene solvate of Compound 1 (Form 3) is characterized as having properties (a), (b), (c), and (d).
  • Figure 7 (b) an X-ray powder diffraction (XRPD) pattern with at least two, four, or all of the characteristic peaks at 12.6 ⁇ 0.1° 2-Theta, 15.4 ⁇ 0.1° 2-Theta, 17.7 ⁇ 0.1° 2-Theta, 24.9 ⁇ 0.1° 2-Theta, 25.4 ⁇ 0.1° 2-Theta, and 26.9 ⁇ 0.1° 2-Theta;
  • XRPD X-ray powder diffraction
  • thermo-gravimetric analysis (TGA) thermogram substantially the same as the one set forth in Figure 8;
  • Compound 1 (Form 4) has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 7.
  • the crystalline form of the hexafluorobenzene solvate of Compound 1 (Form 4) has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 12.6 ⁇ 0.1° 2-Theta, 15.4 ⁇ 0.1° 2-Theta, 17.7 ⁇ 0.1° 2-Theta, 24.9 ⁇ 0.1° 2- Theta, 25.4 ⁇ 0.1° 2-Theta, and 26.9 ⁇ 0.1° 2-Theta.
  • the crystalline form of the hexafluorobenzene solvate of Compound 1 (Form 4) has a DSC thermogram substantially the same as the one set forth in Figure 8. In some embodiments, the crystalline form of the hexafluorobenzene solvate of Compound 1 (Form 4) has a DSC thermogram with an endotherm having an onset at about 84°C and a peak at about 100°C. In some embodiments, the crystalline form of the hexafluorobenzene solvate of Compound 1 (Form 4) has a thermo-gravimetric analysis (TGA) thermogram substantially the same as the one set forth in Figure 8. In some embodiments, the crystalline form of the hexafluorobenzene solvate of Compound 1 (Form 4) is characterized as having properties (a), (b), (c), (d), and (e).
  • a crystalline form (Form 5) of an acetophenone solvate of 1- ((R)-3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l-yl)prop-2- en-l-one that has at least one of the following properties:
  • thermo-gravimetric analysis (TGA) thermogram substantially the same as the one set forth in Figure 10;
  • the crystalline form of the acetophenone solvate of Compound 1 (Form 5) has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 9.
  • the crystalline form of the acetophenone solvate of Compound 1 (Form 5) has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at
  • the crystalline form of the acetophenone solvate of Compound 1 has a DSC thermogram substantially the same as the one set forth in Figure 10.
  • the crystalline form of the acetophenone solvate of Compound 1 (Form 5) has a DSC thermogram with an endotherm having an onset at about 89°C and a peak at about 96°C.
  • the crystalline form of the acetophenone solvate of Compound 1 (Form 5) has a thermo-gravimetric analysis (TGA) thermogram substantially the same as the one set forth in Figure 10.
  • the crystalline form of the acetophenone solvate of Compound 1 (Form 5) has a unit cell parameters approximately equal to the following at a temperature of approximately 100(2) K:
  • the crystalline form of the acetophenone solvate of Compound 1 is characterized as having properties (a), (b), (c), (d), (e), and (f).
  • a crystalline form (Form 6) of a chlorobenzene solvate of l-((R)-3-(4- amino-3 -(4-phenoxyphenyl)- lH-pyrazolo[3 ,4-d]pyrimidin- 1 -yl)piperidin- 1 -yl)prop-2-en- 1 -one that has at least one of the following properties:
  • thermo-gravimetric analysis (TGA) thermogram substantially the same as the one set forth in Figure 12;
  • the crystalline form of the chlorobenzene solvate of Compound 1 has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 11.
  • XRPD X-ray powder diffraction
  • Compound 1 (Form 6) has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 18.4 ⁇ 0.1° 2-Theta, 19.4 ⁇ 0.1° 2-Theta, 20.2 ⁇ 0.1° 2-Theta, 20.9 ⁇ 0.1° 2-Theta, 21.2 ⁇ 0.1°
  • the crystalline form of the chlorobenzene solvate of Compound 1 (Form 6) has a substantially the same X-ray powder diffraction (XRPD) pattern post storage at 40°C and 75% RH for at least a week.
  • the crystalline form of the chlorobenzene solvate of Compound 1 (Form 6) has a DSC thermogram substantially the same as the one set forth in Figure 12.
  • the crystalline form of the chlorobenzene solvate of Compound 1 (Form 6) has a DSC thermogram with an endotherm having an onset at about 92°C and a peak at about 95°C.
  • the crystalline form of the chlorobenzene solvate of Compound 1 (Form 6) has a thermo-gravimetric analysis (TGA) thermogram substantially the same as the one set forth in Figure 12.
  • TGA thermo-gravimetric analysis
  • the crystalline form of the chlorobenzene solvate of Compound 1 (Form 6) is characterized as having properties (a), (b), (c), (d), (e), and (f).
  • thermo-gravimetric analysis (TGA) thermogram substantially the same as the one set forth in Figure 14;
  • the crystalline form of the acetophenone solvate of Compound 1 has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 13.
  • the crystalline form of the acetophenone solvate of Compound 1 (Form 7) has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 6.5 ⁇ 0.1° 2-Theta, 13.0 ⁇ 0.1° 2-Theta, 17.6 ⁇ 0.1° 2-Theta, 18.4 ⁇ 0.1° 2-Theta, 19.9 ⁇ 0.1°
  • the crystalline form of the acetophenone solvate of Compound 1 (Form 7) has a DSC thermogram substantially the same as the one set forth in Figure 14. In some embodiments, the crystalline form of the acetophenone solvate of Compound 1 (Form 7) has a DSC thermogram with an endotherm having an onset at about 124°C and a peak at about 127°C.
  • the crystalline form of the acetophenone solvate of Compound 1 (Form 7) has a thermo-gravimetric analysis (TGA) thermogram substantially the same as the one set forth in Figure 14.
  • TGA thermo-gravimetric analysis
  • the crystalline form of the acetophenone solvate of Compound 1 (Form 7) is characterized as having properties (a), (b), (c), (d), and (e).
  • thermo-gravimetric analysis (TGA) thermogram substantially the same as the one set forth in Figure 16;
  • Compound 1 (Form 8) has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 15.
  • the crystalline form of the dimethylacetamide solvate of Compound 1 (Form 8) has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 8.8 ⁇ 0.1° 2-Theta, 19.2 ⁇ 0.1° 2-Theta, 19.9 ⁇ 0.1° 2-Theta, 22.5 ⁇ 0.1° 2- Theta, 24.5 ⁇ 0.1° 2-Theta, and 25.3 ⁇ 0.1° 2-Theta.
  • the crystalline form of the dimethylacetamide solvate of Compound 1 (Form 8) has a DSC thermogram substantially the same as the one set forth in Figure 16.
  • the crystalline form of the dimethylacetamide solvate of Compound 1 (Form 8) has a DSC thermogram with an endotherm having an onset at about 82°C and a peak at about 85°C.
  • the crystalline form of the dimethylacetamide solvate of Compound 1 (Form 8) has a thermo-gravimetric analysis (TGA) thermogram substantially the same as the one set forth in Figure 16.
  • TGA thermo-gravimetric analysis
  • the crystalline form of the dimethylacetamide solvate of Compound 1 (Form 8) is characterized as having properties (a), (b), (c), (d), (e), and (f).
  • thermo-gravimetric analysis (TGA) thermogram substantially the same as the one set forth in Figure 18;
  • the crystalline form of the benzyl acetate solvate of Compound 1 has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 17.
  • XRPD X-ray powder diffraction
  • Compound 1 (Form 9) has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 12.8 ⁇ 0.1° 2-Theta, 17.8 ⁇ 0.1° 2-Theta, 18.7 ⁇ 0.1° 2-Theta, 19.2 ⁇ 0.1° 2-Theta, 20.1 ⁇ 0.1° 2-Theta, 20.7 ⁇ 0.1° 2-Theta, 21.8 ⁇ 0.1° 2-Theta, 22.1 ⁇ 0.1° 2-Theta and 22.9 ⁇ 0.1° 2-Theta.
  • the crystalline form of the benzyl acetate solvate of Compound 1 (Form 9) has a DSC thermogram substantially the same as the one set forth in Figure 18.
  • the crystalline form of the benzyl acetate solvate of Compound 1 (Form 9) has a DSC thermogram with an endotherm having an onset at about 106°C and a peak at about 108°C and an endotherm having an onset at about 155°C and a peak at about 158°C.
  • the crystalline form of the benzyl acetate solvate of Compound 1 (Form 9) has a thermo-gravimetric analysis (TGA) thermogram substantially the same as the one set forth in Figure 18.
  • TGA thermo-gravimetric analysis
  • Compound 1 (Form 9) is characterized as having properties (a), (b), (c), (d), and (e).
  • crystalline form (Form 10) of a 1,1,2-trichloroethane solvate of l-((R)-3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidin- l-yl)prop-2-en-l-one that has at least one of the following properties:
  • thermo-gravimetric analysis TGA thermogram substantially the same as the one set forth in Figure 20; (f) combinations thereof.
  • the crystalline form of the 1, 1,2-trichloroethane solvate of Compound 1 has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 19.
  • the crystalline form of the 1,1,2-trichloroethane solvate of Compound 1 (Form 10) has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 5.4 ⁇ 0.1° 2-Theta, 18.6 ⁇ 0.1° 2-Theta, 20.1 ⁇ 0.1° 2-Theta, 20.8 ⁇ 0.1° 2- Theta, 21.3 ⁇ 0.1° 2-Theta, 21.7 ⁇ 0.1° 2-Theta, and 22.6 ⁇ 0.1° 2-Theta.
  • the crystalline form of the 1, 1,2-trichloroethane solvate of Compound 1 (Form 10) has a DSC thermogram substantially the same as the one set forth in Figure 20.
  • the crystalline form of the 1, 1,2-trichloroethane solvate of Compound 1 (Form 10) has a DSC thermogram with an endotherm having an onset at about 150°C and a peak at about 154°C.
  • the crystalline form of the 1,1,2-trichloroethane solvate of Compound 1 (Form 10) has a thermo-gravimetric analysis (TGA) thermogram substantially the same as the one set forth in Figure 20.
  • TGA thermo-gravimetric analysis
  • the crystalline form of the 1,1,2- trichloroethane solvate of Compound 1 (Form 10) is characterized as having properties (a), (b), (c), (d), and (e).
  • a pharmaceutically acceptable salt of l-((R)-3-(4- amino-3 -(4-phenoxyphenyl)- lH-pyrazolo[3 ,4-d]pyrimidin- 1 -yl)piperidin- 1 -yl)prop-2-en- 1 -one wherein the pharmaceutically acceptable salt is an acid addition salt.
  • the pharmaceutically acceptable salt is amorphous.
  • the pharmaceutically acceptable salt is crystalline.
  • compositions which include a solvate of
  • the pharmaceutical composition comprises a crystalline form of a butyronitrile solvate of l-((R)-3- (4-amino-3 -(4-phenoxyphenyl)- lH-pyrazolo[3 ,4-d]pyrimidin- 1 -yl)piperidin- 1 -yl)prop-2-en- 1 - one.
  • the pharmaceutical composition comprises a crystalline form of a 1,2-dimethoxy ethane solvate of l-((R)-3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4- d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one.
  • the pharmaceutical composition comprises a crystalline form of a hexafluorobenzene solvate of l-((R)-3-(4-amino-
  • the pharmaceutical composition comprises a crystalline form of a chlorobenzene solvate of l-((R)-3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4- d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one.
  • the pharmaceutical composition comprises a crystalline form of an acetophenone solvate of l-((R)-3-(4-amino-3-(4- phenoxyphenyl)- lH-pyrazolo[3 ,4-d]pyrimidin- 1 -yl)piperidin- 1 -yl)prop-2-en- 1 -one.
  • the pharmaceutical composition comprises a crystalline form of a
  • the pharmaceutical composition comprises a crystalline form of a benzyl acetate solvate of l-((R)-3-(4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3 ,4-d]pyrimidin- 1 -yl)piperidin- 1 -yl)prop-2-en- 1 -one.
  • the pharmaceutical composition comprises a crystalline form of a 1,1,2- trichloroethane solvate of l-((R)-3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4- d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one.
  • the pharmaceutical composition is in a form suitable for oral administration to a mammal.
  • the pharmaceutical composition is an oral solid dosage form.
  • the pharmaceutical composition comprises about 0.5 mg to about 1000 mg of l-((R)-3-(4-amino-3- (4-phenoxyphenyl)- lH-pyrazolo[3 ,4-d]pyrimidin- 1 -yl)piperidin- 1 -yl)prop-2-en- 1 -one solvate.
  • kits for treating a patient by administering a solvate of l-((R)-3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidin- l-yl)prop-2-en-l-one.
  • a method of inhibiting the activity of tyrosine kinase(s), such as Btk, or of treating a disease, disorder, or condition, which would benefit from inhibition of tyrosine kinase(s), such as Btk, in a mammal which includes administering to the mammal a therapeutically effective amount of a solvate of l-((R)-3-(4- amino-3 -(4-phenoxyphenyl)- lH-pyrazolo[3 ,4-d]pyrimidin- 1 -yl)piperidin- 1 -yl)prop-2-en- 1 -one.
  • a solvate of l-((R)-3-(4-amino-3-(4- phenoxyphenyl)- lH-pyrazolo[3 ,4-d]pyrimidin- 1 -yl)piperidin- 1 -yl)prop-2-en- 1 -one for inhibiting Bruton's tyrosine kinase (Btk) activity or for the treatment of a disease, disorder, or condition, which would benefit from inhibition of Bruton's tyrosine kinase (Btk) activity.
  • a solvate of l-((R)-3-(4-amino-3 -(4-phenoxyphenyl)- 1 H- pyrazolo[3,4-d]pyrimidin-l-yl is orally administered.
  • a solvate of 1 -((R)-3-(4-amino-3 -(4-phenoxyphenyl)- 1 H- pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one is used for the formulation of a medicament for the inhibition of tyrosine kinase activity.
  • a solvate of 1 -((R)-3 -(4-amino-3 -(4-phenoxyphenyl)- lH-pyrazolo[3 ,4-d]pyrimi din- 1 -yl)piperidin- 1 - yl)prop-2-en-l-one is used for the formulation of a medicament for the inhibition of Bruton's tyrosine kinase (Btk) activity.
  • a method of treating cancer in a mammal comprising administering to the mammal a pharmaceutical composition described herein comprising a solvate of l-((R)-3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin- l-yl)piperidin-l-yl)prop-2-en-l-one.
  • the cancer is a B cell malignancy.
  • the cancer is a B cell malignancy selected from chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), diffuse large B Cell lymphoma (DLBCL), and multiple myeloma.
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • MCL mantle cell lymphoma
  • DLBCL diffuse large B Cell lymphoma
  • multiple myeloma multiple myeloma.
  • the cancer is a lymphoma, leukemia or a solid tumor.
  • the cancer is diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, burkitt lymphoma/1 eukemi a, or lymphomatoid granulomatosis.
  • follicular lymphoma chronic lymphocytic lymphoma
  • chronic lymphocytic leukemia B-cell prolymphocytic leukemia
  • an anti-cancer agent is administered to the subject in addition to one of the above-mentioned compounds.
  • the anti-cancer agent is an inhibitor of mitogen-activated protein kinase signaling.
  • a method of treating an inflammatory or an autoimmune disease in a mammal comprising administering to the mammal a pharmaceutical composition described herein comprising a solvate of l-((R)-3-(4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one.
  • the inflammatory disease is asthma, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis,
  • the autoimmune disease is inflammatory bowel disease, arthritis, lupus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease Sjogren's syndrome, multiple sclerosis, Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylitisis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, coeliac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, autoimmune hemolytic anemia,
  • composition and methods described herein can be used to treat ischemia/reperfusion injury, such as ischemia/reperfusion injury caused by transplantation, heart attack, stroke, or the like.
  • Articles of manufacture including packaging material, a solvate of l-((R)-3-(4-amino-3- (4-phenoxyphenyl)- lH-pyrazolo[3 ,4-d]pyrimidin- 1 -yl)piperidin- 1 -yl)prop-2-en- 1 -one within the packaging material, and a label that indicates that a solvate of l-((R)-3-(4-amino-3-(4- phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one is used for inhibiting the activity of tyrosine kinase(s), such as Btk, are provided.
  • tyrosine kinase(s) such as Btk
  • a method of treating an autoimmune disease in a mammal comprising administering a solvate of l-((R)-3-(4-amino-3-(4-phenoxyphenyl)-lH- pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one to the mammal.
  • a method of treating a heteroimmune disease or condition in a mammal comprising administering a solvate of l-((R)-3-(4-amino-3-(4- phenoxyphenyl)- lH-pyrazolo[3 ,4-d]pyrimidin- 1 -yl)piperidin- 1 -yl)prop-2-en- 1 -one to the mammal.
  • a method of treating an inflammatory disease in a mammal comprising administering a solvate of l-((R)-3-(4-amino-3-(4-phenoxyphenyl)-lH- pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one to the mammal.
  • a method of treating cancer in a mammal comprising administering a solvate of l-((R)-3-(4-amino-3-(4-phenoxyphenyl)-lH- pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one to the mammal.
  • a method of treating a thromboembolic disorder in a mammal comprising administering a solvate of l-((R)-3-(4-amino-3-(4-phenoxyphenyl)-lH- pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one to the mammal.
  • Thromboembolic disorders include, but are not limited to, myocardial infarct, angina pectoris, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after aortocoronary bypass, restenosis after aortocoronary bypass, stroke, transitory ischemia, a peripheral arterial occlusive disorder, pulmonary embolism, or deep venous thrombosis.
  • methods for modulating, including irreversibly inhibiting, the activity of Btk in a mammal comprising administering to the mammal at least once an effective amount of a solvate of l-((R)-3-(4- amino-3 -(4-phenoxyphenyl)- lH-pyrazolo[3 ,4-d]pyrimidin- 1 -yl)piperidin- 1 -yl)prop-2-en- 1 -one.
  • methods for treating Btk-dependent or Btk mediated conditions or diseases comprising administering to the mammal at least once an effective amount of a solvate of 1- ((R)-3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l-yl)prop-2- en-l-one.
  • methods for treating inflammation comprising administering to the mammal at least once an effective amount of a solvate of l-((R)-3-(4-amino-3-(4- phenoxyphenyl)- lH-pyrazolo[3 ,4-d]pyrimidin- 1 -yl)piperidin- 1 -yl)prop-2-en- 1 -one.
  • a further aspect are methods for the treatment of cancer comprising administering to the mammal at least once an effective amount of a solvate of l-((R)-3-(4-amino-3-(4- phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one.
  • the type of cancer may include, but is not limited to, pancreatic cancer and other solid or hematological tumors.
  • a respiratory disease comprising administering to the mammal at least once an effective amount of a solvate of l-((R)-3-(4-amino-3-(4- phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one.
  • the respiratory disease is asthma.
  • the respiratory disease includes, but is not limited to, adult respiratory distress syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, isocapnic hyperventilation, child-onset asthma, adult-onset asthma, cough-variant asthma, occupational asthma, steroid-resistant asthma, seasonal asthma.
  • methods for preventing rheumatoid arthritis and/or osteoarthritis comprising administering to the mammal at least once an effective amount of a solvate of 1- ((R)-3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l-yl)prop-2- en-l-one.
  • inflammatory responses of the skin comprising administering to the mammal at least once an effective amount of a solvate of l-((R)-3-(4- amino-3 -(4-phenoxyphenyl)- lH-pyrazolo[3 ,4-d]pyrimidin- 1 -yl)piperidin- 1 -yl)prop-2-en- 1 -one.
  • inflammatory responses of the skin include, by way of example, dermatitis, contact dermatitis, eczema, urticaria, rosacea, and scarring.
  • methods for reducing psoriatic lesions in the skin, joints, or other tissues or organs comprising administering to the mammal an effective amount of a solvate of l-((R)-3-(4-amino-3 -(4-phenoxyphenyl)- 1H- pyrazolo[3 ,4-d]pyrimidin- 1 -yl)piperidin- 1 -yl)prop-2-en- 1 -one.
  • a solvate of l-((R)-3-(4-amino-3 -(4-phenoxyphenyl)- 1H- pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one in the manufacture of a medicament for treating an inflammatory disease or condition in an animal in which the activity of Btk or other tyrosine kinases, wherein the other tyrosine kinases share homology with Btk by having a cysteine residue (including a Cys 481 residue) that can form a covalent bond with at least one irreversible inhibitor described herein, contributes to the pathology and/or symptoms of the disease or condition.
  • the tyrosine kinase protein is Btk.
  • the inflammatory disease or conditions are respiratory, cardiovascular, or proliferative diseases.
  • a solvate of 1- ((R)-3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l-yl)prop-2- en-l-one is (a) systemically administered to the mammal; (b) administered orally to the mammal; (c) intravenously administered to the mammal; (d) administered by inhalation; (e) administered by nasal administration; or (f) administered by injection to the mammal; (g) administered topically (dermal) to the mammal; (h) administered by ophthalmic administration; or (i) administered rectally to the mammal.
  • any of the aforementioned aspects are further embodiments comprising single administration of a solvate of l-((R)-3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4- d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one, including further embodiments in which a solvate of 1 -((R)-3 -(4-amino-3 -(4-phenoxyphenyl)- lH-pyrazolo[3 ,4-d]pyrimidin- 1 -yl)piperidin- l-yl)prop-2-en-l-one is administered (i) once; (ii) multiple times over the span of one day; (iii) continually; or (iv) continuously.
  • any of the aforementioned aspects are further embodiments comprising multiple administrations of a solvate of l-((R)-3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4- d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one, including further embodiments in which (i) a solvate of l-((R)-3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidin- l-yl)prop-2-en-l-one is administered in a single dose; (ii) the time between multiple
  • the method comprises a drug holiday, wherein the administration of a solvate of l-((R)-3-(4-amino-3 -(4-phenoxyphenyl)- 1H- pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one is temporarily suspended or the dose of a solvate of l-((R)-3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l- yl)piperidin-l-yl)prop-2-en-l-one being administered is temporarily reduced; at the end of the drug holiday, dosing of a solvate of l-((R)-3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4- d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en
  • a solvate of l-((R)-3-(4-amino-3-(4- phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one is: optically pure (i.e. greater than 99% chiral purity by HPLC).
  • the solvate of l-((R)-3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l- yl)piperidin-l-yl)prop-2-en-l-one is replaced with: a) a solvate of l-((R)-3-(4-amino-3-(4- phenoxyphenyl)- lH-pyrazolo[3 ,4-d]pyrimidin- 1 -yl)piperidin- 1 -yl)prop-2-en- 1 -one of lower chiral purity; b) a solvate of l-((S)-3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4- d]pyrimidin-l-yl)piperid
  • an amorphous form of a solvate of l-((R)-3-(4-amino-3-(4- phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one is used.
  • a crystalline form of a solvate of l-((R)-3-(4-amino-3-(4-phenoxyphenyl)-lH- pyrazolo[3 ,4-d]pyrimidin- 1 -yl)piperidin- 1 -yl)prop-2-en- 1 -one is used.
  • a crystalline form of a butyronitrile solvate of l-((R)-3-(4-amino-3- (4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one is used.
  • a crystalline form of a 1,2-dimethoxy ethane solvate of l-((R)-3-(4-amino-3-(4- phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one is used.
  • a crystalline form of a hexafluorobenzene solvate of l-((R)-3-(4-amino-3-(4- phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one is used.
  • a crystalline form of an acetophenone solvate of l-((R)-3-(4-amino-3-(4- phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one is used.
  • a crystalline form of a chlorobenzene solvate of l-((R)-3-(4-amino-3-(4- phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one is used.
  • a crystalline form of a dimethylacetamide solvate of l-((R)-3-(4-amino-3-(4- phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one is used.
  • a crystalline form of a benzyl acetate solvate of l-((R)-3-(4-amino-3-(4- phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one is used.
  • a crystalline form of a 1,1,2-trichloroethane solvate of l-((R)-3-(4-amino-3-(4- phenoxyphenyl)- lH-pyrazolo[3 ,4-d]pyrimidin- 1 -yl)piperidin- 1 -yl)prop-2-en- 1 -one is used.
  • a solvate of l-((R)-3-(4-amino-3-(4- phenoxyphenyl)- lH-pyrazolo[3 ,4-d]pyrimidin- 1 -yl)piperidin- 1 -yl)prop-2-en- 1 -one, or a pharmaceutically acceptable salt thereof is replaced with an active metabolite of l-((R)-3-(4- amino-3 -(4-phenoxyphenyl)- lH-pyrazolo[3 ,4-d]pyrimidin- 1 -yl)piperidin- 1 -yl)prop-2-en- 1 -one.
  • the active metabolite is in a crystalline form. In some embodiments, the active metabolite is in an amorphous phase. In further embodiments the metabolite is isolated. In some embodiments, in any of the embodiments disclosed herein (including methods, uses, formulations, combination therapy, etc.), a solvate of l-((R)-3-(4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one, or a pharmaceutically acceptable salt thereof, is replaced with a prodrug of l-((R)-3-(4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one, or a deuterated analog of 1- ((R)-3-
  • Figure 1 Illustrates an X-ray powder diffraction (XRPD) pattern of a crystalline form of a butyronitrile solvate of l-((R)-3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin- l-yl)piperidin-l-yl)prop-2-en-l-one (Form 1).
  • XRPD X-ray powder diffraction
  • Figure 2 Illustrates a DSC thermogram and a thermo-gravimetric analysis (TGA) thermogram of a crystalline form of a butyronitrile solvate of l-((R)-3-(4-amino-3-(4- phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one (Form 1).
  • TGA thermo-gravimetric analysis
  • Figure 3 Illustrates an X-ray powder diffraction (XRPD) pattern of a crystalline form of a 1,2-dimethoxy ethane solvate of l-((R)-3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4- d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one (Form 2).
  • XRPD X-ray powder diffraction
  • Figure 4 Illustrates a DSC thermogram and a thermo-gravimetric analysis (TGA) thermogram of a crystalline form of a 1,2-dimethoxy ethane solvate of l-((R)-3-(4-amino-3-(4- phenoxyphenyl)- lH-pyrazolo[3 ,4-d]pyrimidin- 1 -yl)piperidin- 1 -yl)prop-2-en- 1 -one (Form 2).
  • TGA thermo-gravimetric analysis
  • Figure 5 Illustrates an X-ray powder diffraction (XRPD) pattern of a crystalline form of a hexafluorobenzene solvate of l-((R)-3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4- d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one (Form 3).
  • XRPD X-ray powder diffraction
  • Figure 6 Illustrates a DSC thermogram of a crystalline form of a hexafluorobenzene solvate of l-((R)-3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidin- l-yl)prop-2-en-l-one (Form 3).
  • Figure 7 Illustrates an X-ray powder diffraction (XRPD) pattern of a crystalline form of a hexafluorobenzene solvate of l-((R)-3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4- d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one (Form 4).
  • XRPD X-ray powder diffraction
  • Figure 8 Illustrates a DSC thermogram and a thermo-gravimetric analysis (TGA) thermogram a crystalline form of a hexafluorobenzene solvate of l-((R)-3-(4-amino-3-(4- phenoxyphenyl)- lH-pyrazolo[3 ,4-d]pyrimidin- 1 -yl)piperidin- 1 -yl)prop-2-en- 1 -one (Form 4).
  • TGA thermo-gravimetric analysis
  • Figure 9 Illustrates an X-ray powder diffraction (XRPD) pattern of a crystalline form of an acetophenone solvate of l-((R)-3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4- d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one (Form 5).
  • XRPD X-ray powder diffraction
  • thermo-gravimetric analysis TGA thermogram of a crystalline form of an acetophenone solvate of l-((R)-3-(4-amino-3-(4- phenoxyphenyl)- lH-pyrazolo[3 ,4-d]pyrimidin- 1 -yl)piperidin- 1 -yl)prop-2-en- 1 -one (Form 5).
  • Figure 11 Illustrates an X-ray powder diffraction (XRPD) pattern of a crystalline form of a chlorobenzene solvate of l-((R)-3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4- d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one (Form 6).
  • XRPD X-ray powder diffraction
  • Figure 12 Illustrates a DSC thermogram and a thermo-gravimetric analysis (TGA) thermogram of a crystalline form of a chlorobenzene solvate of l-((R)-3-(4-amino-3-(4- phenoxyphenyl)- lH-pyrazolo[3 ,4-d]pyrimidin- 1 -yl)piperidin- 1 -yl)prop-2-en- 1 -one (Form 6).
  • TGA thermo-gravimetric analysis
  • Figure 13 Illustrates an X-ray powder diffraction (XRPD) pattern of a crystalline form of an acetophenone solvate of l-((R)-3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4- d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one (Form 7).
  • XRPD X-ray powder diffraction
  • Figure 14 Illustrates a DSC thermogram and a thermo-gravimetric analysis (TGA) thermogram of a crystalline form of an acetophenone solvate of l-((R)-3-(4-amino-3-(4- phenoxyphenyl)- lH-pyrazolo[3 ,4-d]pyrimidin- 1 -yl)piperidin- 1 -yl)prop-2-en- 1 -one (Form 7).
  • TGA thermo-gravimetric analysis
  • Figure 15 Illustrates an X-ray powder diffraction (XRPD) pattern of a crystalline form of a dimethylacetamide solvate of l-((R)-3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4- d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one (Form 8).
  • XRPD X-ray powder diffraction
  • Figure 16 Illustrates a DSC thermogram and a thermo-gravimetric analysis (TGA) thermogram of a crystalline form of a dimethylacetamide solvate of l-((R)-3-(4-amino-3-(4- phenoxyphenyl)- lH-pyrazolo[3 ,4-d]pyrimidin- 1 -yl)piperidin- 1 -yl)prop-2-en- 1 -one (Form 8).
  • TGA thermo-gravimetric analysis
  • Figure 17 Illustrates an X-ray powder diffraction (XRPD) pattern of a crystalline form of a benzyl acetate solvate of l-((R)-3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4- d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one (Form 9).
  • XRPD X-ray powder diffraction
  • Figure 18 Illustrates a DSC thermogram and a thermo-gravimetric analysis (TGA) thermogram of crystalline of a benzyl acetate solvate of l-((R)-3-(4-amino-3-(4- phenoxyphenyl)- lH-pyrazolo[3 ,4-d]pyrimidin- 1 -yl)piperidin- 1 -yl)prop-2-en- 1 -one (Form 9).
  • TGA thermo-gravimetric analysis
  • Figure 19 Illustrates an X-ray powder diffraction (XRPD) pattern of a crystalline form of a 1,1,2-trichloroethane solvate of l-((R)-3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4- d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one (Form 10).
  • XRPD X-ray powder diffraction
  • Figure 20 Illustrates a DSC thermogram and a thermo-gravimetric analysis (TGA) thermogram of a crystalline form of a 1,1,2-trichloroethane solvate of l-((R)-3-(4-amino-3-(4- phenoxyphenyl)- lH-pyrazolo[3 ,4-d]pyrimidin- 1 -yl)piperidin- 1 -yl)prop-2-en- 1 -one (Form 10).
  • TGA thermo-gravimetric analysis
  • Btk signaling in various hematopoietic cell functions, e.g., B-cell receptor activation, suggests that small molecule Btk inhibitors, such as Compound 1, are useful for reducing the risk of or treating a variety of diseases affected by or affecting many cell types of the hematopoetic lineage including, e.g., autoimmune diseases, heteroimmune conditions or diseases, inflammatory diseases, cancer (e.g., B-cell proliferative disorders), and thromboembolic disorders.
  • irreversible Btk inhibitor compounds such as Compound 1
  • a solvate of l-((R)-3-(4-amino-3-(4-phenoxyphenyl)-lH- pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one can be used in the treatment of an autoimmune disease in a mammal, which includes, but is not limited to, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, lupus, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease Sjogren's syndrome, multiple sclerosis, Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylitisis, antiphospholipid antibody syndrome, a
  • a solvate of Compound 1 can be used in the treatment of a heteroimmune disease or condition in a mammal, which include, but are not limited to graft versus host disease, transplantation, transfusion, anaphylaxis, allergies (e.g., allergies to plant pollens, latex, drugs, foods, insect poisons, animal hair, animal dander, dust mites, or cockroach calyx), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis.
  • a heteroimmune disease or condition in a mammal which include, but are not limited to graft versus host disease, transplantation, transfusion, anaphylaxis, allergies (e.g., allergies to plant pollens, latex, drugs, foods, insect poisons, animal hair, animal dander, dust mites, or cockroach calyx), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic derma
  • a solvate of Compound 1 can be used in the treatment of an inflammatory disease in a mammal, which includes, but is not limited to asthma, inflammatory bowel disease, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis,
  • a solvate of Compound 1 described herein can be used to treat hematological malignancies such as, but not limited to, a leukemia, a lymphoma, a myeloma, a non-Hodgkin's lymphoma, a Hodgkin's lymphoma, a T-cell malignancy, or a B-cell
  • the hematological malignancy is a treatment naive hematological malignancy. In some embodiments the hematological malignancy is a relapsed or refractory hematological malignancy.
  • the methods described herein can be used to treat a cancer, e.g., B-cell proliferative disorders, which include, but are not limited to diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), lymphoplasmacytic lymphoma, B cell prolymphocytic leukemia, intravascular large B cell lymphoma, primary effusion lymphoma, burkitt
  • thromboembolic disorders which include, but are not limited to myocardial infarct, angina pectoris (including unstable angina), reocclusions or restenoses after angioplasty or
  • aortocoronary bypass stroke, transitory ischemia, peripheral arterial occlusive disorders, pulmonary embolisms, and deep venous thromboses.
  • a method for treating a hematological malignancy in an individual in need thereof comprising: administering to the individual an amount of a solvate of Compound 1.
  • the hematological malignancy is a non-Hodgkin's lymphoma (NHL).
  • the hematological malignancy is a chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, or a non-CLL/SLL lymphoma.
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • high risk CLL or a non-CLL/SLL lymphoma.
  • the hematological malignancy is follicular lymphoma (FL), diffuse large B- cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma (MM), marginal zone lymphoma, Burkitt' s lymphoma, non-Burkitt high grade B cell lymphoma, or extranodal marginal zone B cell lymphoma.
  • the hematological malignancy is acute or chronic myelogenous (or myeloid) leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia, or precursor B-cell acute
  • the hematological malignancy is chronic lymphocytic leukemia (CLL). In some embodiments, the hematological malignancy is mantle cell lymphoma (MCL). In some embodiments, the hematological malignancy is diffuse large B- cell lymphoma (DLBCL). In some embodiments, the hematological malignancy is diffuse large B-cell lymphoma (DLBCL), ABC subtype. In some embodiments, the hematological malignancy is diffuse large B-cell lymphoma (DLBCL), GCB subtype. In some embodiments, the hematological malignancy is Waldenstrom's macroglobulinemia (WM). In some embodiments, WM.
  • WM Waldenstrom's macroglobulinemia
  • the hematological malignancy is multiple myeloma (MM). In some embodiments, the hematological malignancy is Burkitt's lymphoma. In some embodiments, the hematological malignancy is follicular lymphoma (FL). In some embodiments, the hematological malignancy is transformed follicular lymphoma. In some embodiments, the hematological malignancy is marginal zone lymphoma.
  • the hematological malignancy is relapsed or refractory non- Hodgkin's lymphoma (NHL).
  • the hematological malignancy is relapsed or refractory diffuse large B-cell lymphoma (DLBCL), relapsed or refractory mantle cell lymphoma (MCL), relapsed or refractory follicular lymphoma (FL), relapsed or refractory CLL, relapsed or refractory SLL, relapsed or refractory multiple myeloma, relapsed or refractory Waldenstrom's macroglobulinemia, relapsed or refractory multiple myeloma (MM), relapsed or refractory marginal zone lymphoma, relapsed or refractory Burkitt's lymphoma, relapsed or refractory non-Burkitt high grade B cell
  • the hematological malignancy is a relapsed or refractory acute or chronic myelogenous (or myeloid) leukemia, relapsed or refractory myelodysplastic syndrome, relapsed or refractory acute lymphoblastic leukemia, or relapsed or refractory precursor B-cell acute lymphoblastic leukemia.
  • the hematological malignancy is a relapsed or refractory acute or chronic myelogenous (or myeloid) leukemia, relapsed or refractory myelodysplastic syndrome, relapsed or refractory acute lymphoblastic leukemia, or relapsed or refractory precursor B-cell acute lymphoblastic leukemia.
  • the hematological malignancy is a relapsed or refractory acute or chronic myelogenous (or myeloid) leukemia, relapsed or refractory myelodysplastic syndrome, relapse
  • hematological malignancy is relapsed or refractory chronic lymphocytic leukemia (CLL). In some embodiments, the hematological malignancy is relapsed or refractory mantle cell lymphoma (MCL). In some embodiments, the hematological malignancy is relapsed or refractory diffuse large B-cell lymphoma (DLBCL). In some embodiments, the hematological malignancy is relapsed or refractory diffuse large B-cell lymphoma (DLBCL), ABC subtype. In some embodiments, the hematological malignancy is relapsed or refractory diffuse large B-cell lymphoma (DLBCL), GCB subtype.
  • CLL chronic lymphocytic leukemia
  • MCL mantle cell lymphoma
  • DLBCL refractory diffuse large B-cell lymphoma
  • DLBCL refractory diffuse large B-cell lymphoma
  • the hematological malignancy is relapsed or refractory Waldenstrom's macroglobulinemia (WM). In some embodiments, the hematological malignancy is relapsed or refractory multiple myeloma (MM). In some embodiments, the hematological malignancy is relapsed or refractory Burkitt's lymphoma. In some embodiments, the hematological malignancy is relapsed or refractory follicular lymphoma (FL).
  • WM Waldenstrom's macroglobulinemia
  • MM multiple myeloma
  • the hematological malignancy is relapsed or refractory Burkitt's lymphoma.
  • the hematological malignancy is relapsed or refractory follicular lymphoma (FL).
  • the hematological malignancy is a hematological malignancy that is classified as high-risk. In some embodiments, the hematological malignancy is high risk CLL or high risk SLL.
  • the hematologic malignancy is a T-cell malignancy.
  • the T-cell malignancy is peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), anaplastic large cell lymphoma, angioimmunoblastic lymphoma, cutaneous T-cell lymphoma, adult T-cell leukemia/lymphoma (ATLL), blastic NK-cell lymphoma, enteropathy - type T-cell lymphoma, hematosplenic gamma-delta T-cell lymphoma, lymphoblastic lymphoma, nasal NK/T-cell lymphomas, or treatment-related T-cell lymphomas.
  • the T-cell malignancy is a relapsed or refractory T-cell malignancy.
  • the T- cell malignancy is a treatment naive T-cell malignancy.
  • BCLDs B-cell lymphoproliferative disorders
  • BCLDs can originate either in the lymphatic tissues (as in the case of lymphoma) or in the bone marrow (as in the case of leukemia and myeloma), and they all are involved with the uncontrolled growth of lymphocytes or white blood cells.
  • There are many subtypes of BCLD e.g., chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL).
  • CLL chronic lymphocytic leukemia
  • NHL non-Hodgkin lymphoma
  • Malignant lymphomas are neoplastic transformations of cells that reside predominantly within lymphoid tissues.
  • Two groups of malignant lymphomas are Hodgkin's lymphoma and non-Hodgkin's lymphoma (NHL). Both types of lymphomas infiltrate reticuloendothelial tissues. However, they differ in the neoplastic cell of origin, site of disease, presence of systemic symptoms, and response to treatment (Freedman et al., "Non-Hodgkin's Lymphomas" Chapter 134, Cancer Medicine, (an approved publication of the American Cancer Society, B.C. Decker Inc., Hamilton, Ontario, 2003).
  • Hodgkin's lymphoma in an individual in need thereof comprising: administering to the individual an amount of a solvate of Compound 1.
  • the non-Hodgkin's lymphoma is relapsed or refractory diffuse large B- cell lymphoma (DLBCL), relapsed or refractory mantle cell lymphoma, relapsed or refractory follicular lymphoma, or relapsed or refractory CLL.
  • DLBCL diffuse large B- cell lymphoma
  • Non-Hodgkin lymphomas are a diverse group of malignancies that are predominately of B-cell origin. NHL may develop in any organs associated with lymphatic system such as spleen, lymph nodes or tonsils and can occur at any age. NHL is often marked by enlarged lymph nodes, fever, and weight loss. NHL is classified as either B-cell or T-cell NHL. Lymphomas related to lymphoproliferative disorders following bone marrow or stem cell transplantation are usually B-cell NHL.
  • NHL has been divided into low-, intermediate-, and high-grade categories by virtue of their natural histories (see “The Non-Hodgkin's Lymphoma Pathologic Classification Project," Cancer 49(1982):2112-2135).
  • the low-grade lymphomas are indolent, with a median survival of 5 to 10 years (Horning and Rosenberg (1984) N. Engl. J. Med. 311 : 1471-1475).
  • a non-limiting list of the B-cell NHL includes Burkitt's lymphoma (e.g., Tb's lymphoma).
  • Lymphoma Cutaneous Marginal Zone Lymphoma (MZL), Diffuse Large Cell Lymphoma (DLBCL), Diffuse Mixed Small and Large Cell Lymphoma, Diffuse Small Cleaved Cell, Diffuse Small Lymphocytic Lymphoma, Extranodal Marginal Zone B-cell lymphoma, follicular lymphoma, Follicular Small Cleaved Cell (Grade 1), Follicular Mixed Small Cleaved and Large Cell (Grade 2), Follicular Large Cell (Grade 3), Intravascular Large B-Cell Lymphoma, Intravascular Lymphomatosis, Large Cell Immunoblastic Lymphoma, Large Cell Lymphoma (LCL), Lymphoblastic Lymphoma, MALT Lymphoma, Mantle Cell Lymphoma (MCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia (
  • lymphoplasmocytic lymphoma hairy cell leukemia, Waldenstrom's Macroglobulinemia, and primary central nervous system (CNS) lymphoma. Additional non-Hodgkin's lymphomas are contemplated within the scope of the present invention and apparent to those of ordinary skill in the art.
  • a method for treating a DLCBL in an individual in need thereof comprising: administering to the individual an amount of a solvate of Compound 1.
  • a method for treating relapsed or refractory DLCBL in an individual in need thereof comprising: administering to the individual a therapeutically-effective amount of a solvate of Compound 1.
  • DLBCL Diffuse large B-cell lymphoma
  • DLBCL is further divided into subtypes: activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL), germinal center diffuse large B-cell lymphoma (GCB DLBCL), and Double-Hit (DH) DLBCL.
  • ABC-DLBCL is characterized by a CD79B mutation.
  • ABC-DLBCL is characterized by a CD79A mutation.
  • the ABC-DLBCL is characterized by a mutation in MyD88, A20, or a combination thereof.
  • B-cell lymphoma, activated B cell-like subtype (ABC-DLBCL), in an individual in need thereof, comprising: administering to the individual an irreversible Btk inhibitor in an amount from 300 mg/day up to, and including, 1000 mg/day.
  • the ABC subtype of diffuse large B-cell lymphoma (ABC-DLBCL) is thought to arise from post germinal center B cells that are arrested during plasmatic differentiation.
  • the ABC subtype of DLBCL (ABC-DLBCL) accounts for
  • ABC-DLBCL is most commonly associated with chromosomal translocations deregulating the germinal center master regulator BCL6 and with mutations inactivating the PRDM1 gene, which encodes a transcriptional repressor required for plasma cell differentiation.
  • a particularly relevant signaling pathway in the pathogenesis of ABC-DLBCL is the one mediated by the nuclear factor ( F)-KB transcription complex.
  • the F- ⁇ family comprises 5 members (p50, p52, p65, c-rel and RelB) that form homo- and heterodimers and function as transcriptional factors to mediate a variety of proliferation, apoptosis, inflammatory and immune responses and are critical for normal B-cell development and survival.
  • F- ⁇ is widely used by eukaryotic cells as a regulator of genes that control cell proliferation and cell survival. As such, many different types of human tumors have misregulated F- ⁇ : that is, NF- KB is constitutively active. Active F- ⁇ turns on the expression of genes that keep the cell proliferating and protect the cell from conditions that would otherwise cause it to die via apoptosis.
  • ABC DLBCLs The dependence of ABC DLBCLs on F-kB depends on a signaling pathway upstream of IkB kinase comprised of CARD11, BCL10 and MALTl (the CBM complex). Interference with the CBM pathway extinguishes NF-kB signaling in ABC DLBCL cells and induces apoptosis.
  • the molecular basis for constitutive activity of the NF-kB pathway is a subject of current investigation but some somatic alterations to the genome of ABC DLBCLs clearly invoke this pathway.
  • somatic mutations of the coiled-coil domain of CARD 11 in DLBCL render this signaling scaffold protein able to spontaneously nucleate protein-protein interaction with MALTl and BCL10, causing IKK activity and NF-kB activation.
  • Constitutive activity of the B cell receptor signaling pathway has been implicated in the activation of NF-kB in ABC DLBCLs with wild type CA D11, and this is associated with mutations within the cytoplasmic tails of the B cell receptor subunits CD79A and CD79B.
  • Oncogenic activating mutations in the signaling adapter MYD88 activate NF-kB and synergize with B cell receptor signaling in sustaining the survival of ABC DLBCL cells.
  • inactivating mutations in a negative regulator of the NF-kB pathway, A20 occur almost exclusively in ABC DLBCL.
  • DLBCL cells of the ABC subtype such as OCI-LylO, have chronic active BCR signaling and are very sensitive to the Btk inhibitor described herein.
  • induction of apoptosis, as shown by capsase activation, Annexin-V flow cytometry and increase in sub-GO fraction is observed in OCILylO.
  • Both sensitive and resistant cells express Btk at similar levels, and the active site of Btk is fully occupied by the inhibitor in both as shown using a fluorescently labeled affinity probe.
  • OCI-LylO cells are shown to have chronically active BCR signaling to NF-kB which is dose dependently inhibited by the Btk inhibitors described herein.
  • Btk inhibitors in the cell lines studied herein are also characterized by comparing signal transduction profiles (Btk, PLCy, ERK, NF-kB, AKT), cytokine secretion profiles and mRNA expression profiles, both with and without BCR stimulation, and observed significant differences in these profiles that lead to clinical biomarkers that identify the most sensitive patient populations to Btk inhibitor treatment. See U.S. Patent No. 7,711,492 and Staudt et al., Nature, Vol. 463, Jan. 7, 2010, pp. 88-92, the contents of which are incorporated by reference in their entirety.
  • a method for treating a follicular lymphoma in an individual in need thereof comprising: administering to the individual an amount of a solvate of Compound 1.
  • a method for treating relapsed or refractory follicular lymphoma in an individual in need thereof comprising: administering to the individual a therapeutically-effective amount of a solvate of Compound 1.
  • follicular lymphoma refers to any of several types of non-Hodgkin's lymphoma in which the lymphomatous cells are clustered into nodules or follicles.
  • the term follicular is used because the cells tend to grow in a circular, or nodular, pattern in lymph nodes. The average age for people with this lymphoma is about 60.
  • a method for treating a CLL or SLL in an individual in need thereof comprising: administering to the individual an amount of a solvate of Compound 1.
  • a method for treating relapsed or refractory CLL or SLL in an individual in need thereof comprising:
  • CLL/SLL Chronic lymphocytic leukemia and small lymphocytic lymphoma
  • SLL small lymphocytic lymphoma
  • CLL and SLL are slow-growing diseases, although CLL, which is much more common, tends to grow slower.
  • CLL and SLL are treated the same way. They are usually not considered curable with standard treatments, but depending on the stage and growth rate of the disease, most patients live longer than 10 years. Occasionally over time, these slow-growing lymphomas may transform into a more aggressive type of lymphoma.
  • CLL Chronic lymphoid leukemia
  • chemotherapy chemotherapy, radiation therapy, biological therapy, or bone marrow transplantation.
  • Symptoms are sometimes treated surgically (splenectomy removal of enlarged spleen) or by radiation therapy ("de-bulking" swollen lymph nodes).
  • CLL progresses slowly in most cases, it is considered generally incurable. Certain CLLs are classified as high- risk.
  • high risk CLL means CLL characterized by at least one of the following 1) 17pl3-; 2) 1 lq22-; 3) unmutated IgVH together with ZAP-70+ and/or CD38+; or 4) trisomy 12.
  • CLL treatment is typically administered when the patient's clinical symptoms or blood counts indicate that the disease has progressed to a point where it may affect the patient's quality of life.
  • Small lymphocytic leukemia is very similar to CLL described supra, and is also a cancer of B-cells. In SLL the abnormal lymphocytes mainly affect the lymph nodes.
  • SLL non-Hodgkin lymphoma
  • SLL indolent lymphoma
  • SLL responds well to a variety of chemotherapy drugs, it is generally considered to be incurable.
  • some cancers tend to occur more often in one gender or the other, cases and deaths due to SLL are evenly split between men and women.
  • the average age at the time of diagnosis is 60 years.
  • SLL is indolent, it is persistently progressive.
  • the usual pattern of this disease is one of high response rates to radiation therapy and/or chemotherapy, with a period of disease remission. This is followed months or years later by an inevitable relapse. Re-treatment leads to a response again, but again the disease will relapse.
  • the instant invention fulfills this long standing need in the art.
  • a method for treating a Mantle cell lymphoma in an individual in need thereof comprising: administering to the individual an amount of a solvate of Compound 1.
  • a method for treating relapsed or refractory Mantle cell lymphoma in an individual in need thereof comprising: administering to the individual a therapeutically-effective amount of a solvate of Compound 1.
  • Mantle cell lymphoma refers to a subtype of B-cell lymphoma, due to CD5 positive antigen-naive pregerminal center B-cell within the mantle zone that surrounds normal germinal center follicles. MCL cells generally over-express cyclin Dl due to a t( 11 : 14) chromosomal translocation in the DNA. More specifically, the translocation is at t(l I;14)(ql3;q32). Only about 5% of lymphomas are of this type. The cells are small to medium in size. Men are affected most often. The average age of patients is in the early 60s. The lymphoma is usually widespread when it is diagnosed, involving lymph nodes, bone marrow, and, very often, the spleen. Mantle cell lymphoma is not a very fast growing lymphoma, but is difficult to treat.
  • a method for treating a marginal zone B-cell lymphoma in an individual in need thereof comprising: administering to the individual an amount of a solvate of Compound 1.
  • a method for treating relapsed or refractory marginal zone B-cell lymphoma in an individual in need thereof comprising: administering to the individual a therapeutically- effective amount of a solvate of Compound 1.
  • marginal zone B-cell lymphoma refers to a group of related B-cell neoplasms that involve the lymphoid tissues in the marginal zone, the patchy area outside the follicular mantle zone.
  • Marginal zone lymphomas account for about 5% to 10% of lymphomas. The cells in these lymphomas look small under the microscope.
  • There are 3 main types of marginal zone lymphomas including extranodal marginal zone B-cell lymphomas, nodal marginal zone B-cell lymphoma, and splenic marginal zone lymphoma.
  • a method for treating a MALT in an individual in need thereof comprising: administering to the individual an amount of a solvate of Compound 1.
  • a method for treating relapsed or refractory MALT in an individual in need thereof comprising: administering to the individual a therapeutically-effective amount of a solvate of Compound 1.
  • MALT lymphoma refers to extranodal manifestations of marginal-zone lymphomas. Most MALT lymphoma are a low grade, although a minority either manifest initially as intermediate-grade non-Hodgkin lymphoma (NHL) or evolve from the low-grade form. Most of the MALT lymphoma occur in the stomach, and roughly 70% of gastric MALT lymphoma are associated with Helicobacter pylori infection. Several cytogenetic abnormalities have been identified, the most common being trisomy 3 or t(l 1; 18). Many of these other MALT lymphoma have also been linked to infections with bacteria or viruses. The average age of patients with MALT lymphoma is about 60.
  • a method for treating a nodal marginal zone B-cell lymphoma in an individual in need thereof comprising: administering to the individual an amount of a solvate of Compound 1.
  • a method for treating relapsed or refractory nodal marginal zone B-cell lymphoma in an individual in need thereof comprising: administering to the individual a therapeutically-effective amount of a solvate of Compound 1.
  • nodal marginal zone B-cell lymphoma refers to an indolent B-cell lymphoma that is found mostly in the lymph nodes.
  • the disease is rare and only accounts for 1% of all Non-Hodgkin' s Lymphomas (NHL). It is most commonly diagnosed in older patients, with women more susceptible than men.
  • the disease is classified as a marginal zone lymphoma because the mutation occurs in the marginal zone of the B-cells. Due to its confinement in the lymph nodes, this disease is also classified as nodal.
  • a method for treating a splenic marginal zone B-cell lymphoma in an individual in need thereof comprising: administering to the individual an amount of a solvate of Compound 1.
  • a method for treating relapsed or refractory splenic marginal zone B-cell lymphoma in an individual in need thereof comprising: administering to the individual a therapeutically-effective amount of a solvate of Compound 1.
  • splenic marginal zone B-cell lymphoma refers to specific low-grade small B-cell lymphoma that is incorporated in the World Health Organization classification. Characteristic features are splenomegaly, moderate lymphocytosis with villous morphology, intrasinusoidal pattern of involvement of various organs, especially bone marrow, and relative indolent course. Tumor progression with increase of blastic forms and aggressive behavior are observed in a minority of patients. Molecular and cytogenetic studies have shown heterogeneous results probably because of the lack of standardized diagnostic criteria.
  • a method for treating a Burkitt lymphoma in an individual in need thereof comprising: administering to the individual an amount of a solvate of Compound 1.
  • a method for treating relapsed or refractory Burkitt lymphoma in an individual in need thereof comprising: administering to the individual a therapeutically-effective amount of a solvate of Compound 1.
  • Burkitt lymphoma refers to a type of Non-Hodgkin Lymphoma
  • Burkitt's lymphoma that commonly affects children. It is a highly aggressive type of B-cell lymphoma that often starts and involves body parts other than lymph nodes. In spite of its fast-growing nature, Burkitt's lymphoma is often curable with modern intensive therapies. There are two broad types of Burkitt's lymphoma - the sporadic and the endemic varieties:
  • EBV Epstein Barr Virus
  • Sporadic Burkitt's lymphoma The type of Burkitt's lymphoma that affects the rest of the world, including Europe and the Americas is the sporadic type. Here too, it's mainly a disease in children.
  • Epstein Barr Virus (EBV) is not as strong as with the endemic variety, though direct evidence of EBV infection is present in one out of five patients. More than the involvement of lymph nodes, it is the abdomen that is notably affected in more than 90% of the children. Bone marrow involvement is more common than in the sporadic variety.
  • Waldenstrom Macroglobulinemia is a method for treating a Waldenstrom macroglobulinemia in an individual in need thereof, comprising: administering to the individual an amount of a solvate of Compound 1. Further disclosed herein, in certain embodiments, is a method for treating relapsed or refractory Waldenstrom macroglobulinemia in an individual in need thereof, comprising: administering to the individual a therapeutically-effective amount of a solvate of Compound 1.
  • lymphoplasmacytic lymphoma cancer involving a subtype of white blood cells called lymphocytes. It is characterized by an uncontrolled clonal proliferation of terminally differentiated B lymphocytes. It is also characterized by the lymphoma cells making an antibody called immunoglobulin M (IgM).
  • IgM immunoglobulin M
  • the IgM antibodies circulate in the blood in large amounts, and cause the liquid part of the blood to thicken, like syrup. This can lead to decreased blood flow to many organs, which can cause problems with vision (because of poor circulation in blood vessels in the back of the eyes) and neurological problems (such as headache, dizziness, and confusion) caused by poor blood flow within the brain.
  • a method for treating a myeloma in an individual in need thereof comprising: administering to the individual an amount of a solvate of Compound 1.
  • a method for treating relapsed or refractory myeloma in an individual in need thereof comprising: administering to the individual a therapeutically-effective amount of a solvate of Compound 1.
  • myeloma also known as MM, myeloma, plasma cell myeloma, or as
  • Kahler's disease (after Otto Kahler) is a cancer of the white blood cells known as plasma cells.
  • a type of B cell, plasma cells are a crucial part of the immune system responsible for the production of antibodies in humans and other vertebrates. They are produced in the bone marrow and are transported through the lymphatic system.
  • a method for treating a leukemia in an individual in need thereof comprising: administering to the individual an amount of a solvate of Compound 1.
  • a method for treating relapsed or refractory leukemia in an individual in need thereof comprising: administering to the individual a therapeutically-effective amount of a solvate of Compound 1.
  • Leukemia is a cancer of the blood or bone marrow characterized by an abnormal increase of blood cells, usually leukocytes (white blood cells).
  • Leukemia is a broad term covering a spectrum of diseases. The first division is between its acute and chronic forms: (i) acute leukemia is characterized by the rapid increase of immature blood cells. This crowding makes the bone marrow unable to produce healthy blood cells. Immediate treatment is required in acute leukemia due to the rapid progression and accumulation of the malignant cells, which then spill over into the bloodstream and spread to other organs of the body. Acute forms of leukemia are the most common forms of leukemia in children; (ii) chronic leukemia is distinguished by the excessive build up of relatively mature, but still abnormal, white blood cells.
  • the cells are produced at a much higher rate than normal cells, resulting in many abnormal white blood cells in the blood.
  • Chronic leukemia mostly occurs in older people, but can theoretically occur in any age group. Additionally, the diseases are subdivided according to which kind of blood cell is affected.
  • lymphoblastic or lymphocytic leukemias the cancerous change takes place in a type of marrow cell that normally goes on to form lymphocytes, which are infection-fighting immune system cells;
  • myeloid or myelogenous leukemias the cancerous change takes place in a type of marrow cell that normally goes on to form red blood cells, some other types of white cells, and platelets.
  • ALL Acute lymphoblastic leukemia
  • precursor B-cell acute lymphoblastic leukemia precursor B-cell acute lymphoblastic leukemia
  • AML Acute myelogenous leukemia
  • CML Chronic myelogenous leukemia
  • HCL Hairy cell leukemia
  • a method for treating Acute lymphoblastic leukemia ALL
  • precursor B-cell acute lymphoblastic leukemia precursor B- ALL; also called precursor B-lymphoblastic leukemia
  • AML Acute myelogenous leukemia
  • CML Chronic myelogenous leukemia
  • HCL Hairy cell leukemia
  • the leukemia is a relapsed or refractory leukemia.
  • the leukemia is a relapsed or refractory Acute lymphoblastic leukemia (ALL), relapsed or refractory precursor B-cell acute lymphoblastic leukemia (precursor B-ALL; also called precursor B-lymphoblastic leukemia), relapsed or refractory Acute myelogenous leukemia (AML), relapsed or refractory Chronic myelogenous leukemia (CML), or relapsed or refractory Hairy cell leukemia (HCL).
  • ALL Acute lymphoblastic leukemia
  • precursor B-ALL also called precursor B-lymphoblastic leukemia
  • AML Acute myelogenous leukemia
  • CML Chronic myelogenous leukemia
  • HCL Hairy cell leukemia
  • irreversible Btk inhibitor compounds such as a solvate of Compound 1, for treating any of the foregoing diseases.
  • the therapeutic efficacy of a solvate of Compound 1 for any one of the foregoing diseases can be optimized during a course of treatment.
  • a subject being treated can undergo a diagnostic evaluation to correlate the relief of disease symptoms or pathologies to inhibition of in vivo Btk activity achieved by administering a given dose of Compound 1 in a solvate form.
  • Cellular assays known in the art can be used to determine in vivo activity of Btk in the presence or absence of an irreversible Btk inhibitor. For example, since activated Btk is phosphorylated at tyrosine 223 (Y223) and tyrosine 551 (Y551), phospho-specific
  • immunocytochemical staining of P-Y223 or P-Y551 -positive cells can be used to detect or quantify activation of Btk in a population of cells (e.g., by FACS analysis of stained vs unstained cells). See, e.g., Nisitani et al. (1999), Proc. Natl. Acad. Sci, USA 96:2221-2226.
  • the amount of the Btk inhibitor compound that is administered to a subject can be increased or decreased as needed so as to maintain a level of Btk inhibition optimal for treating the subject's disease state.
  • Compound 1 can irreversibly inhibit Btk and may be used to treat mammals suffering from Bruton's tyrosine kinase-dependent or Bruton's tyrosine kinase mediated conditions or diseases, including, but not limited to, cancer, autoimmune and other inflammatory diseases.
  • Compound 1 has shown efficacy in a wide variety of diseases and conditions that are described herein.
  • a solvate of Compound 1 is used for the manufacture of a medicament for treating any of the foregoing conditions (e.g., autoimmune diseases,
  • a solvate of Compound 1 described herein can be used to treat a solid tumor.
  • a solvate of Compound 1 described herein can be used to treat carcinoma of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung, vagina, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone or thyroid, sarcoma, glioblastomas, neuroblastomas, multiple myeloma, gastrointestinal cancer, especially colon carcinoma or colorectal adenoma, a tumor of the neck and head, an epidermal hyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, a neoplasia of epithelial character, adenoma, adenocarcinoma, keratoacan
  • the composition is for use in treatment of a sarcoma or carcinoma. In some embodiments, the composition is for use in treatment of a sarcoma. In some embodiments, the composition is for use in treatment of a carcinoma. In some embodiments, the sarcoma is selected from alveolar rhabdomyosarcoma; alveolar soft part sarcoma;
  • ameloblastoma angiosarcoma; chondrosarcoma; chordoma; clear cell sarcoma of soft tissue; dedifferentiated liposarcoma; desmoid; desmoplastic small round cell tumor; embryonal rhabdomyosarcoma; epithelioid fibrosarcoma; epithelioid hemangioendothelioma; epithelioid sarcoma; esthesioneuroblastoma; Ewing sarcoma; extrarenal rhabdoid tumor; extraskeletal myxoid chondrosarcoma; extrasketetal osteosarcoma; fibrosarcoma; giant cell tumor;
  • hemangiopericytoma infantile fibrosarcoma; inflammatory myofibroblastic tumor; Kaposi sarcoma; leiomyosarcoma of bone; liposarcoma; liposarcoma of bone; malignant fibrous histiocytoma (MFH); malignant fibrous histiocytoma (MFH) of bone; malignant
  • mesenchymoma malignant peripheral nerve sheath tumor; mesenchymal chondrosarcoma; myxofibrosarcoma; myxoid liposarcoma; myxoinflammatory fibroblastic sarcoma; neoplasms with perivascular epitheioid cell differentiation; osteosarcoma; parosteal osteosarcoma;
  • neoplasm with perivascular epitheioid cell differentiation periosteal osteosarcoma; pleomorphic liposarcoma; pleomorphic rhabdomyosarcoma; P ET/extraskeletal Ewing tumor;
  • the carcinoma is selected from an adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, or small cell carcinoma.
  • the solid tumor is selected from anal cancer; appendix cancer; bile duct cancer (i.e., cholangiocarcinoma); bladder cancer; brain tumor; breast cancer; HER2-amplified breast cancer; cervical cancer; colon cancer; cancer of Unknown Primary (CUP); esophageal cancer; eye cancer; fallopian tube cancer; kidney cancer; renal cell carcinoma; liver cancer; lung cancer; medulloblastoma;
  • anal cancer i.e., cholangiocarcinoma
  • bladder cancer i.e., cholangiocarcinoma
  • brain tumor HER2-amplified breast cancer
  • cervical cancer colon cancer
  • cancer of Unknown Primary (CUP) Unknown Primary
  • esophageal cancer eye cancer
  • fallopian tube cancer kidney cancer; renal cell carcinoma; liver cancer; lung cancer; medulloblastoma
  • medulloblastoma medulloblastoma
  • the carcinoma is breast cancer.
  • the breast cancer is invasive ductal carcinoma, ductal carcinoma in situ, invasive lobular carcinoma, or lobular carcinoma in situ.
  • the carcinoma is pancreatic cancer.
  • the pancreatic cancer is adenocarcinoma, or islet cell carcinoma.
  • the carcinoma is colorectal cancer.
  • the colorectal cancer is adenocarcinoma.
  • the solid tumor is a colon polyp.
  • the colon polyp is associated with familial adenomatous polyposis.
  • the carcinoma is bladder cancer.
  • the bladder cancer is transitional cell bladder cancer, squamous cell bladder cancer, or adenocarcinoma.
  • the carcinoma is lung cancer.
  • the lung cancer is a non- small cell lung cancer.
  • the non-small cell lung cancer is adenocarcinoma, squamous-cell lung carcinoma, or large-cell lung carcinoma.
  • the non-small cell lung cancer is large eel lung cancer.
  • the lung cancer is a small cell lung cancer.
  • the carcinoma is prostate cancer.
  • the prostate cancer is adenocarcinoma or small cell carcinoma.
  • the carcinoma is ovarian cancer.
  • the ovarian cancer is epithelial ovarian cancer.
  • the carcinoma is bile duct cancer.
  • the bile duct cancer is proximal bile duct carcinoma or distal bile duct carcinoma.
  • composition and methods described herein can be used to treat mastocytosis.
  • a solvate of Compound 1 described herein can be used to treat a central nervous system (CNS) malignancy.
  • the CNS malignancy is a primary CNS lymphoma.
  • the primary CNS lymphoma is a glioma.
  • the glioma is astrocytomas, ependymomas, oligodendrogliomas.
  • the CNS malignancy is astrocytic tumors such as juvenile pilocytic,
  • anaplastic astrocytoma glioblastoma multiforme
  • ependymal tumors such as myxopapillary and well-differentiated ependymoma, anaplastic ependymoma, ependymoblastoma
  • oligodendroglial tumors including well-differentiated oligodendroglioma and anaplastic oligodendroglioma
  • mixed tumors such as mixed astrocytoma-ependymoma, mixed astrocytoma-oligodendroglioma, mixed astrocytomaependymoma-oligodendroglioma; or medulloblastoma.
  • a solvate of Compound 1 described herein can be used to treat fibrosis.
  • the fibrosis is not associated with graft versus host disease (GVHD).
  • the fibrosis is not associated with sclerodermatous GVHD, lung chronic GVHD, or liver chronic GVHD.
  • the fibrosis is of the liver, lung, pancreas, kidney, bone marrow, heart, skin, intestine, or joints.
  • the fibrosis is of the liver.
  • the fibrosis is of the lung.
  • the fibrosis is of the pancreas.
  • the patient has cirrhosis, chronic pancreatitis, or cystic fibrosis.
  • Btk and kinases having a cysteine residue in an amino acid sequence position of the tyrosine kinase that is homologous to the amino acid sequence position of cysteine 481 in Btk can form a covalent bond with Cys 481 of Btk (e.g., via a Michael reaction).
  • a wide variety of pharmaceutically acceptable salts is formed from Compound 1 and includes:
  • - acid addition salts formed by reacting Compound 1 with an organic acid which includes aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyl alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, amino acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, critric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,
  • compositions in reference to Compound 1 refers to a salt of Compound 1, which does not cause significant irritation to a mammal to which it is administered and does not substantially abrogate the biological activity and properties of the compound.
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are formed during the process of product formation or isolation with pharmaceutically acceptable solvents such as water, ethanol, methanol, methyl tert-butyl ether (MTBE), diisopropyl ether (DIPE), ethyl acetate, isopropyl acetate, isopropyl alcohol, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), acetone, nitromethane, tetrahydrofuran (THF), dichloromethane (DCM), dioxane, heptanes, toluene, anisole, acetonitrile, acetophenone, benzyl acetate, butyronitrile, chlorobenzene, 1,2-dimethoxy ethane, dimethylacetamide,
  • solvents such as water, ethanol, methanol,
  • solvates are formed using, but not limited to, Class 3 solvent(s). Categories of solvents are defined in, for example, the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), "Impurities: Guidelines for Residual Solvents,
  • solvates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.
  • solvates of Compound 1, or pharmaceutically acceptable salts thereof are prepared or formed by the processes described herein.
  • solvates of Compound 1 are anhydrous. It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms (solvates).
  • a solvate of Compound 1, or a pharmaceutically acceptable salt thereof is prepared in various forms, including but not limited to, amorphous phase, crystalline forms, milled forms and nano-particulate forms.
  • a solvate of Compound 1, or a pharmaceutically acceptable salt thereof is amorphous.
  • a solvate of Compound 1, or a pharmaceutically acceptable salt thereof is amorphous and anhydrous.
  • a pharmaceutically acceptable salt thereof is crystalline.
  • a solvate of Compound 1, or a pharmaceutically acceptable salt thereof is crystalline and anhydrous.
  • a solvate of Compound 1, or a pharmaceutically acceptable salt thereof is comtemplated to provide improved solubility and/or bioavailability.
  • a solvate of Compound 1, or a pharmaceutically acceptable salt thereof is stable.
  • a solvate of Compound 1, or a pharmaceutically acceptable salt thereof converts to a more stable crystalline form of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, and may be useful in the preparation, such as purification, of Compound 1 or the more stable crystalline form of Compound 1, or a pharmaceutically acceptable salt or solvate thereof.
  • Compound 1 is prepared as outlined in US Patent no.
  • Compound 1 is a butyronitrile solvate.
  • the butyronitrile solvate of Compound 1 is crystalline Form 1.
  • the crystalline form of the butyronitrile solvate of Compound 1 (Form 1) is characterized as having at least one of the following properties:
  • thermo-gravimetric analysis (TGA) thermogram substantially the same as the one set forth in Figure 2;
  • Compound 1 (Form 1) is characterized as having at least two of the properties selected from (a) to (e).
  • the crystalline form of the butyronitrile solvate of Compound 1 (Form 1) is characterized as having at least three of the properties selected from (a) to (e).
  • the crystalline form of the butyronitrile solvate of Compound 1 (Form 1) is characterized as having at least four of the properties selected from (a) to (e).
  • the crystalline form of the butyronitrile solvate of Compound 1 (Form 1) is characterized as having properties (a) to (e).
  • Compound 1 (Form 1) has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 1.
  • the crystalline form of the butyronitrile solvate of Compound 1 (Form 1) has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 2.7 ⁇ 0.1° 2-Theta, 5.5 ⁇ 0.1° 2-Theta, 10.9 ⁇ 0.1° 2-Theta, 13.6 ⁇ 0.1° 2-Theta, 14.8 ⁇ 0.1° 2- Theta, 17.3 ⁇ 0.1° 2-Theta, 18.7 ⁇ 0.1° 2-Theta, 20.0 ⁇ 0.1° 2-Theta, and 21.8 ⁇ 0.1° 2-Theta.
  • Compound 1 (Form 1) has a DSC thermogram substantially the same as the one set forth in
  • the crystalline form of the butyronitrile solvate of Compound 1 (Form 1) has a DSC thermogram with an endotherm at between about 100-125°C.
  • the endotherm event have an onset at about 110 °C, a first peak at about 120 °C and a second peak at about 121 °C.
  • the DSC thermogram further has an endotherm having an onset at about 153°C and a peak at about 156°C.
  • the crystalline form of the butyronitrile solvate of Compound 1 (Form 1) has a thermo- gravimetric analysis (TGA) thermogram substantially the same as the one set forth in Figure 2. 1,2-Dimethoxyethane solvate of Compound 1, crystalline Form 2
  • a Compound 1 1,2-dimethoxy ethane solvate is provided.
  • the 1,2-dimethoxy ethane solvate of Compound 1 is crystalline Form 2.
  • the crystalline form of the 1,2-dimethoxy ethane solvate of Compound 1 (Form 2) is
  • thermo-gravimetric analysis (TGA) thermogram substantially the same as the one set forth in Figure 4;
  • Compound 1 (Form 2) is characterized as having at least two of the properties selected from (a) to (f).
  • Compound 1 (Form 2) is characterized as having at least three of the properties selected from (a) to (f).
  • the crystalline form of the 1,2-dimethoxy ethane solvate of Compound 1 (Form 2) is characterized as having at least four of the properties selected from (a) to (f).
  • the crystalline form of the 1,2-dimethoxy ethane solvate of Compound 1 (Form 2) is characterized as having at least five of the properties selected from (a) to (f).
  • the crystalline form of the 1,2-dimethoxy ethane solvate of Compound 1 (Form 2) is characterized as having properties (a) to (f).
  • Compound 1 (Form 2) has an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 3.
  • the crystalline form of the 1,2-dimethoxy ethane solvate of Compound 1 (Form 2) has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 6.8 ⁇ 0.1° 2-Theta, 13.4 ⁇ 0.1° 2-Theta, 17.6 ⁇ 0.1° 2-Theta, 18.2 ⁇ 0.1° 2- Theta, 20.2 ⁇ 0.1° 2-Theta, 21.2 ⁇ 0.1° 2-Theta, and 22.2 ⁇ 0.1° 2-Theta.
  • the crystalline form of the 1,2-dimethoxy ethane solvate of Compound 1 has substantially the same X-ray powder diffraction (XRPD) pattern post storage at 40°C and 75% RH for at least a week.
  • Compound 1 (Form 2) has a DSC thermogram substantially the same as the one set forth in Figure 4.
  • the crystalline form of the 1,2-dimethoxy ethane solvate of Compound 1 (Form 2) has a DSC thermogram with an endotherm having an onset at about 89°C and a peak at about 101°C.
  • the crystalline form of the 1,2- dimethoxyethane solvate of Compound 1 (Form 2) has a thermo-gravimetric analysis (TGA) thermogram substantially the same as the one set forth in Figure 4.
  • a Compound 1 hexafluorobenzene solvate In some embodiments, provided is a Compound 1 hexafluorobenzene solvate. In some embodiments, the hexafluorobenzene solvate of Compound 1 is crystalline Form 3. The crystalline form of the hexafluorobenzene solvate of Compound 1 (Form 3) is characterized as having at least one of the following properties:
  • Compound 1 (Form 3) is characterized as having at least two of the properties selected from (a) to (d).
  • Compound 1 (Form 3) is characterized as having at least three of the properties selected from (a) to (d).
  • Compound 1 (Form 3) is characterized as having properties (a) to (d).
  • Compound 1 (Form 3) has an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 5.
  • the crystalline form of the hexafluorobenzene solvate of Compound 1 (Form 3) has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 5.4 ⁇ 0.1° 2-Theta, 14.0 ⁇ 0.1° 2-Theta, 16.1 ⁇ 0.1° 2-Theta, 18.6 ⁇ 0.1° 2- Theta, 19.3 ⁇ 0.1° 2-Theta, 22.4 ⁇ 0.1° 2-Theta, and 23.6 ⁇ 0.1° 2-Theta.
  • Compound 1 (Form 3) has a DSC thermogram substantially the same as the one set forth in
  • the crystalline form of the hexafluorobenzene solvate of Compound 1 has a DSC thermogram with an endotherm having an onset at about 51°C.
  • a Compound 1 hexafluorobenzene solvate is provided.
  • the hexafluorobenzene solvate of Compound 1 is crystalline Form 4.
  • the crystalline form of the hexafluorobenzene solvate of Compound 1 (Form 4) is characterized as having at least one of the following properties:
  • thermo-gravimetric analysis (TGA) thermogram substantially the same as the one set forth in Figure 8;
  • Compound 1 (Form 4) is characterized as having at least two of the properties selected from (a) to (e).
  • Compound 1 (Form 4) is characterized as having at least three of the properties selected from (a) to (e). In some embodiments, the crystalline form of the hexafluorobenzene solvate of
  • Compound 1 (Form 4) is characterized as having at least four of the properties selected from (a) to (e).
  • Compound 1 (Form 4) is characterized as having properties (a) to (e).
  • Compound 1 (Form 4) has an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 7.
  • the crystalline form of the hexafluorobenzene solvate of Compound 1 (Form 4) has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 12.6 ⁇ 0.1° 2-Theta, 15.4 ⁇ 0.1° 2-Theta, 17.7 ⁇ 0.1° 2-Theta, 24.9 ⁇ 0.1° 2- Theta, 25.4 ⁇ 0.1° 2-Theta, and 26.9 ⁇ 0.1° 2-Theta.
  • Compound 1 (Form 4) has a DSC thermogram substantially the same as the one set forth in
  • the crystalline form of the hexafluorobenzene solvate of Compound 1 (Form 4) has a DSC thermogram with an endotherm having an onset at about 84°C and a peak at about 100°C.
  • the crystalline form of the hexafluorobenzene solvate of Compound 1 (Form 4) has a thermo-gravimetric analysis (TGA) thermogram substantially the same as the one set forth in Figure 8.
  • a Compound 1 acetophenone solvate In some embodiments, provided is a Compound 1 acetophenone solvate. In some embodiments, the acetophenone solvate of Compound 1 is crystalline Form 5. In some embodiments, the crystalline form of the acetophenone solvate of Compound 1 (Form 5) is characterized as having at least one of the following properties:
  • thermo-gravimetric analysis (TGA) thermogram substantially the same as the one set forth in Figure 10;
  • Compound 1 (Form 5) is characterized as having at least two of the properties selected from (a) to (f).
  • the crystalline form of the acetophenone solvate of Compound 1 (Form 5) is characterized as having at least three of the properties selected from (a) to (f).
  • the crystalline form of the acetophenone solvate of Compound 1 (Form 5) is characterized as having at least four of the properties selected from (a) to (f).
  • the crystalline form of the acetophenone solvate of Compound 1 (Form 5) is characterized as having at least five of the properties selected from (a) to (f).
  • the crystalline form of the acetophenone solvate of Compound 1 is characterized as having properties (a) to (f).
  • Compound 1 (Form 5) has an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 9.
  • the crystalline form of the acetophenone solvate of Compound 1 (Form 5) has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 7.6 ⁇ 0.1° 2-Theta, 8.8 ⁇ 0.1° 2-Theta, 15.2 ⁇ 0.1° 2-Theta, 17.6 ⁇ 0.1° 2-Theta, 18.9 ⁇ 0.1° 2- Theta, 19.5 ⁇ 0.1° 2-Theta, 20.4 ⁇ 0.1° 2-Theta, 21.0 ⁇ 0.1° 2-Theta, 21.3 ⁇ 0.1° 2-Theta, 21.8 ⁇ 0.1° 2-Theta, 24.3 ⁇ 0.1° 2-Theta, and 24.8 ⁇ 0.1° 2-Theta. [00191]
  • Compound 1 (Form 5) has a DSC thermogram substantially the same as the one set forth in Figure 10.
  • Compound 1 (Form 5) has a DSC thermogram with an endotherm having an onset at about 89°C and a peak at about 96°C.
  • endotherm event of the crystalline form of the acetophenone solvate of Compound 1 (Form 5) is between about 50-110°C.
  • the crystalline form of the acetophenone solvate of Compound 1 has a thermo-gravimetric analysis (TGA) thermogram substantially the same as the one set forth in Figure 10.
  • TGA thermo-gravimetric analysis
  • Compound 1 (Form 5) has unit cell parameters approximately equal to the following at a temperature of approximately 100(2) K:
  • a Compound 1 chlorobenzene solvate In some embodiments, provided is a Compound 1 chlorobenzene solvate. In some embodiments, the chlorobenzene solvate of Compound 1 is crystalline Form 6. In some embodiments, the crystalline form of the chlorobenzene solvate of Compound 1 (Form 6) is characterized as having at least one of the following properties:
  • thermo-gravimetric analysis (TGA) thermogram substantially the same as the one set forth in Figure 12;
  • Compound 1 (Form 6) is characterized as having at least two of the properties selected from (a) to (f).
  • the crystalline form of the chlorobenzene solvate of Compound 1 (Form 6) is characterized as having at least three of the properties selected from (a) to (f).
  • the crystalline form of the chlorobenzene solvate of Compound 1 (Form 6) is characterized as having at least four of the properties selected from (a) to (f).
  • the crystalline form of the chlorobenzene solvate of Compound 1 (Form 6) is characterized as having at least five of the properties selected from (a) to (f).
  • the crystalline form of the chlorobenzene solvate of Compound 1 is characterized as having properties (a) to (f).
  • Compound 1 (Form 6) has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 11.
  • the crystalline form of the chlorobenzene solvate of Compound 1 (Form 6) has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 18.4 ⁇ 0.1° 2-Theta, 19.4 ⁇ 0.1° 2-Theta, 20.2 ⁇ 0.1° 2-Theta, 20.9 ⁇ 0.1° 2-Theta, 21.2 ⁇ 0.1° 2-Theta, 21.9 ⁇ 0.1° 2-Theta, and 25.0 ⁇ 0.1° 2-Theta.
  • Compound 1 (Form 6) has a DSC thermogram substantially the same as the one set forth in
  • Compound 1 (Form 6) has a DSC thermogram with an endotherm having an onset at about 92°C and a peak at about 95°C.
  • the crystalline form of the chlorobenzene solvate of Compound 1 (Form 6) has a thermo-gravimetric analysis (TGA) thermogram substantially the same as the one set forth in Figure 12.
  • a Compound 1 acetophenone solvate In some embodiments, provided is a Compound 1 acetophenone solvate. In some embodiments, the acetophenone solvate of Compound 1 is crystalline Form 7. In some embodiments, the crystalline form of the acetophenone solvate of Compound 1 (Form 7) is characterized as having at least one of the following properties: (a) an X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure
  • thermo-gravimetric analysis (TGA) thermogram substantially the same as the one set forth in Figure 14;
  • Compound 1 (Form 7) is characterized as having at least two of the properties selected from (a) to (e). In some embodiments, the crystalline form of the acetophenone solvate of Compound 1 (Form 7) is characterized as having at least three of the properties selected from (a) to (e). In some embodiments, the crystalline form of the acetophenone solvate of Compound 1 (Form 7) is characterized as having at least four of the properties selected from (a) to (e). In some embodiments, the crystalline form of the acetophenone solvate of Compound 1 (Form 7) is characterized as having properties (a) to (e).
  • Compound 1 (Form 7) has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 13.
  • the crystalline form of the acetophenone solvate of Compound 1 (Form 7) has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 6.5 ⁇ 0.1° 2-Theta, 13.0 ⁇ 0.1° 2-Theta, 17.6 ⁇ 0.1° 2-Theta, 17.9 ⁇ 0.1° 2-Theta, 18.4 ⁇ 0.1° 2-Theta, 19.9 ⁇ 0.1° 2-Theta, 21.0 ⁇ 0.1° 2-Theta, 21.5 ⁇ 0.1° 2-Theta, 22.1 ⁇ 0.1° 2-Theta, 23.3 ⁇ 0.1° 2-Theta and 23.9 ⁇ 0.1° 2-Theta.
  • Compound 1 (Form 7) has a DSC thermogram substantially the same as the one set forth in Figure 14.
  • Compound 1 (Form 7) has a DSC thermogram with an endotherm having an onset at about 124°C and a peak at about 127°C.
  • acetophenone solvate of Compound 1 has a thermo-gravimetric analysis (TGA) thermogram substantially the same as the one set forth in Figure 14.
  • TGA thermo-gravimetric analysis
  • a Compound 1 dimethylacetamide solvate is provided.
  • the dimethylacetamide solvate of Compound 1 is crystalline Form 8.
  • the crystalline form of the dimethylacetamide solvate of Compound 1 is characterized as having at least one of the following properties:
  • thermo-gravimetric analysis (TGA) thermogram substantially the same as the one set forth in Figure 16;
  • Compound 1 (Form 8) is characterized as having at least two of the properties selected from (a) to (f).
  • Compound 1 (Form 8) is characterized as having at least three of the properties selected from (a) to (f). In some embodiments, the crystalline form of the dimethylacetamide solvate of
  • Compound 1 (Form 8) is characterized as having at least four of the properties selected from (a) to (f).
  • Compound 1 (Form 8) is characterized as having at least five of the properties selected from (a) to (f).
  • Compound 1 (Form 8) is characterized as having properties (a) to (f).
  • Compound 1 (Form 8) has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 15.
  • the crystalline form of the dimethylacetamide solvate of Compound 1 (Form 8) has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 8.8 ⁇ 0.1° 2-Theta, 19.2 ⁇ 0.1° 2-Theta, 19.9 ⁇ 0.1° 2-Theta, 22.5 ⁇ 0.1° 2- Theta, 24.5 ⁇ 0.1° 2-Theta, and 25.3 ⁇ 0.1° 2-Theta.
  • Compound 1 (Form 8) has a DSC thermogram substantially the same as the one set forth in Figure 16.
  • the crystalline form of the dimethylacetamide solvate of Compound 1 (Form 8) has a DSC thermogram with an endotherm having an onset at about 82°C and a peak at about 85°C.
  • the crystalline form of the dimethylacetamide solvate of Compound 1 (Form 8) has a thermo-gravimetric analysis (TGA) thermogram substantially the same as the one set forth in Figure 16.
  • TGA thermo-gravimetric analysis
  • the crystalline form of the dimethylacetamide solvate of Compound 1 (Form 8) has unit cell parameters approximately equal to the following at a temperature of approximately 100(2) K:
  • a Compound 1 benzyl acetate solvate In some embodiments, provided is a Compound 1 benzyl acetate solvate. In some embodiments, the benzyl acetate solvate of Compound 1 is crystalline Form 9. In some embodiments, the crystalline form of the benzyl acetate solvate of Compound 1 (Form 9) is characterized as having at least one of the following properties: (a) X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 17;
  • thermo-gravimetric analysis (TGA) thermogram substantially the same as the one set forth in Figure 18;
  • Compound 1 (Form 9) is characterized as having at least two of the properties selected from (a) to (e).
  • the crystalline form of the benzyl acetate solvate of Compound 1 (Form 9) is characterized as having at least three of the properties selected from (a) to (e).
  • the crystalline form of the benzyl acetate solvate of Compound 1 (Form 9) is characterized as having at least four of the properties selected from (a) to (e).
  • the crystalline form of the benzyl acetate solvate of Compound 1 (Form 9) is characterized as having at least five of the properties selected from (a) to (e).
  • the crystalline form of the benzyl acetate solvate of Compound 1 (Form 9) is characterized as having properties (a) to (e).
  • Compound 1 (Form 9) has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 17.
  • the crystalline form of the benzyl acetate solvate of Compound 1 (Form 9) has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 12.8 ⁇ 0.1° 2-Theta, 17.8 ⁇ 0.1° 2-Theta, 18.7 ⁇ 0.1° 2-Theta, 19.2 ⁇ 0.1° 2-Theta, 20.1 ⁇ 0.1° 2-Theta, 20.7 ⁇ 0.1° 2-Theta, 22.1 ⁇ 0.1° 2-Theta and 22.9 ⁇ 0.1° 2-Theta.
  • Compound 1 (Form 9) has a DSC thermogram substantially the same as the one set forth in Figure 18.
  • Compound 1 (Form 9) has a DSC thermogram with an endotherm having an onset at about 106°C and a peak at about 108°C and an endotherm having an onset at about 155°C and a peak at about 158°C .
  • the crystalline form of the benzyl acetate solvate of Compound 1 (Form 9) has a thermo-gravimetric analysis (TGA) thermogram substantially the same as the one set forth in Figure 18.
  • TGA thermo-gravimetric analysis
  • the crystalline form of the benzyl acetate solvate of Compound 1 does not change after storage at 40°C and 75%RH.
  • the benzyl acetate solvate of Compound 1 (Form 9) is a hemi-solvate.
  • a Compound 1 1, 1,2-trichloroethane solvate.
  • the 1, 1,2-trichloroethane solvate of Compound 1 is crystalline Form 10.
  • the crystalline form of the 1, 1,2-trichloroethane solvate of Compound 1 (Form 10) is characterized as having at least one of the following properties:
  • thermo-gravimetric analysis (TGA) thermogram substantially the same as the one set forth in Figure 20;
  • Compound 1 (Form 10) is characterized as having at least two of the properties selected from (a) to (e).
  • Compound 1 (Form 10) is characterized as having at least three of the properties selected from (a) to (e).
  • the crystalline form of the 1,1,2-trichloroethane solvate of Compound 1 (Form 10) is characterized as having at least four of the properties selected from (a) to (e).
  • the crystalline form of the 1,1,2-trichloroethane solvate of Compound 1 (Form 10) is characterized as having at least five of the properties selected from (a) to (e).
  • Compound 1 (Form 10) is characterized as having properties (a) to (e).
  • Compound 1 has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 19.
  • the crystalline form of the 1, 1,2-trichloroethane solvate of Compound 1 (Form 10) has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 5.4 ⁇ 0.1° 2-Theta, 18.6 ⁇ 0.1° 2-Theta, 20.1 ⁇ 0.1° 2-Theta, 20.8 ⁇ 0.1° 2- Theta, 21.3 ⁇ 0.1° 2-Theta, 21.7 ⁇ 0.1° 2-Theta, and 22.6 ⁇ 0.1° 2-Theta.
  • Compound 1 (Form 10) has a DSC thermogram substantially the same as the one set forth in Figure 20.
  • the crystalline form of the 1, 1,2-trichloroethane solvate of Compound 1 (Form 10) has a DSC thermogram with an endotherm having an onset at about 64°C and a peak at about 80°C, and an endotherm having an onset at about 150°C and a peak at about 154°C.
  • the crystalline form of the 1, 1,2-trichloroethane solvate of Compound 1 (Form 10) has a thermo-gravimetric analysis (TGA) thermogram substantially the same as the one set forth in Figure 20.
  • TGA thermo-gravimetric analysis
  • the crystalline form of the 1,1,2- trichloroethane solvate of Compound 1 changes to a Form A after storage at 40°C and 75%RH.
  • the molar ratio of 1,1,2-trichloroethane and Compound 1 in the crystalline form is about 0.3 to 0.4, e.g., about 0.34.
  • solvated crystalline forms of l-((R)-3-(4-amino-3-(4- phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one are prepared as outlined in the Examples. It is noted that solvents, temperatures and other reaction conditions presented herein may vary.
  • GMP Good Manufacturing Practice
  • Preferred solvents are those that are suitable for use in GMP facilities and consistent with industrial safety concerns. Categories of solvents are defined in, for example, the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), "Impurities: Guidelines for Residual Solvents,
  • Solvents are categorized into three classes. Class 1 solvents are toxic and are to be avoided. Class 2 solvents are solvents to be limited in use during the manufacture of the therapeutic agent. Class 3 solvents are solvents with low toxic potential and of lower risk to human health. Data for Class 3 solvents indicate that they are less toxic in acute or short-term studies and negative in genotoxicity studies.
  • Class 1 solvents which are to be avoided, include: benzene; carbon tetrachloride; 1,2-dichloroethane; 1,1-dichloroethene; and 1, 1,1-trichloroethane.
  • Class 2 solvents are: acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethene, dichloromethane, 1,2-dimethoxy ethane, N,N- dimethylacetamide, ⁇ , ⁇ -dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethyleneglycol, formamide, hexane, methanol, 2-methoxyethanol, methylbutyl ketone, methylcyclohexane, N- methylpyrrolidine, nitromethane, pyridine, sulfolane, tetrahydrofuran, tetralin, toluene, 1, 1,2- trichloroethene and xylene.
  • Class 3 solvents which possess low toxicity, include: acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butylmethyl ether (MTBE), cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3 -methyl- 1-butanol, methylethyl ketone,
  • Residual solvents in active pharmaceutical ingredients originate from the manufacture of API. In some cases, the solvents are not completely removed by practical manufacturing techniques. Appropriate selection of the solvent for the synthesis of APIs may enhance the yield, or determine characteristics such as crystal form, purity, and solubility.
  • the solvent is a critical parameter in the synthetic process.
  • compositions comprising Compound 1 comprise an organic solvent(s). In some embodiments, compositions comprising Compound 1 comprise a residual amount of an organic solvent(s). In some embodiments, compositions comprising Compound 1 comprise a residual amount of a Class 2 solvent. In some embodiments, compositions comprising Compound 1 comprise a residual amount of a Class 3 solvent. In some embodiments, the organic solvent is a Class 3 solvent.
  • the Class 3 solvent is selected from the group consisting of acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butylmethyl ether, cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3- methyl- 1-butanol, methylethyl ketone, methylisobutyl ketone, 2-methyl-l-propanol, pentane, 1- pentanol, 1-propanol, 2-propanol, propyl acetate, and tetrahydrofuran.
  • the Class 3 solvent is selected from ethyl acetate, isopropyl acetate, tert-butylmethylether,
  • solvents include acetophenone, benzonitrile, benzyl acetate, benzyl alcohol, t-butanol, butyronitrile, chlorobenzotrifluoride, cyclopentylmethyl ether,
  • agonist refers to a compound, the presence of which results in a biological activity of a protein that is the same as the biological activity resulting from the presence of a naturally occurring ligand for the protein, such as, for example, Btk.
  • partial agonist refers to a compound the presence of which results in a biological activity of a protein that is of the same type as that resulting from the presence of a naturally occurring ligand for the protein, but of a lower magnitude.
  • the term "antagonist” refers to a compound, the presence of which results in a decrease in the magnitude of a biological activity of a protein.
  • the presence of an antagonist results in complete inhibition of a biological activity of a protein, such as, for example, Btk.
  • an antagonist is an inhibitor.
  • amelioration of the symptoms of a particular disease, disorder or condition by administration of a particular compound or pharmaceutical composition refers to any lessening of severity, delay in onset, slowing of progression, or shortening of duration, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the compound or composition.
  • Bioavailability refers to the percentage of Compound 1 dosed that is delivered into the general circulation of the animal or human being studied. The total exposure (AUC( 0 . ⁇ )) of a drug when administered intravenously is usually defined as 100% bioavailable (F%).
  • Oral bioavailability refers to the extent to which Compound 1 is absorbed into the general circulation when the pharmaceutical composition is taken orally as compared to intravenous injection.
  • Blood plasma concentration refers to the concentration of Compound 1 in the plasma component of blood of a subject. It is understood that the plasma concentration of Compound 1 may vary significantly between subjects, due to variability with respect to metabolism and/or possible interactions with other therapeutic agents. In accordance with one embodiment disclosed herein, the blood plasma concentration of Compound 1 may vary from subject to subject. Likewise, values such as maximum plasma concentration (C maX ) or time to reach maximum plasma concentration (T max ), or total area under the plasma concentration time curve (AUC(o-oo)) may vary from subject to subject. Due to this variability, the amount necessary to constitute "a therapeutically effective amount" of Compound 1 may vary from subject to subject.
  • Bruton's tyrosine kinase refers to Bruton's tyrosine kinase from Homo sapiens, as disclosed in, e.g., U.S. Patent No. 6,326,469 (GenBank Accession No. NP_000052).
  • Bruton's tyrosine kinase homolog refers to orthologs of Bruton's tyrosine kinase, e.g., the orthologs from mouse (GenBank Acession No.
  • NP_001007799 chicken (GenBank Acession No. NP_989564), or zebra fish (GenBank Acession No. XP 698117), and fusion proteins of any of the foregoing that exhibit kinase activity towards one or more substrates of Bruton's tyrosine kinase (e.g. a peptide substrate having the amino acid sequence "AVLESEEELYSSARQ").
  • co-administration are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.
  • an “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an “effective amount” for therapeutic uses is the amount of the composition including a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms without undue adverse side effects.
  • An appropriate “effective amount” in any individual case may be determined using techniques, such as a dose escalation study.
  • the term "therapeutically effective amount” includes, for example, a prophylactically effective amount.
  • an “effective amount” of a compound disclosed herein is an amount effective to achieve a desired pharmacologic effect or therapeutic improvement without undue adverse side effects. It is understood that “an effect amount” or “a therapeutically effective amount” can vary from subject to subject, due to variation in metabolism of Compound 1, age, weight, general condition of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician. By way of example only, therapeutically effective amounts may be determined by routine experimentation, including but not limited to a dose escalation clinical trial.
  • the terms “enhance” or “enhancing” means to increase or prolong either in potency or duration a desired effect.
  • “enhancing” the effect of therapeutic agents refers to the ability to increase or prolong, either in potency or duration, the effect of therapeutic agents on during treatment of a disease, disorder or condition.
  • An “enhancing- effective amount,” as used herein, refers to an amount adequate to enhance the effect of a therapeutic agent in the treatment of a disease, disorder or condition. When used in a patient, amounts effective for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.
  • cysteine 482 is the homologous cysteine of the rat ortholog of Bruton's tyrosine kinase
  • cysteine 479 is the homologous cysteine of the chicken ortholog
  • cysteine 481 is the homologous cysteine in the zebra fish ortholog.
  • the homologous cysteine of TXK is Cys 350.
  • Other examples of kinases having homologous cysteines are shown in FIG. 1. See also the sequence alignments of tyrosine kinases (TK) published on the world wide web at kinase . com/human/kinome/phylogeny .html .
  • characteristic peaks refers to peaks that are distinguishable from the baseline noise.
  • characteristic peaks refers to peaks having an area, height, or intensity that is at least 30 %, at least 25 % or at least 20 % of the peak having the largest area, height, or intensity, respectively.
  • the term “about” or “ ⁇ ” when used before a numerical value indicates that the value may vary within a reasonable range, such as within ⁇ 10%, ⁇ 5% or ⁇ 1% of the stated value.
  • inhibitors refer to inhibition of enzymatic phosphotransferase activity.
  • irreversible inhibitor refers to a compound that, upon contact with a target protein (e.g., a kinase) causes the formation of a new covalent bond with or within the protein, whereby one or more of the target protein's biological activities (e.g., phosphotransferase activity) is diminished or abolished notwithstanding the subsequent presence or absence of the irreversible inhibitor.
  • a target protein e.g., a kinase
  • biological activities e.g., phosphotransferase activity
  • irreversible Btk inhibitor refers to an inhibitor of Btk that can form a covalent bond with an amino acid residue of Btk.
  • the irreversible inhibitor of Btk can form a covalent bond with a Cys residue of Btk; in particular embodiments, the irreversible inhibitor can form a covalent bond with a Cys 481 residue (or a homolog thereof) of Btk or a cysteine residue in the homologous corresponding position of another tyrosine kinase.
  • isolated refers to separating and removing a component of interest from components not of interest. Isolated substances can be in either a dry or semi-dry state, or in solution, including but not limited to an aqueous solution.
  • the isolated component can be in a homogeneous state or the isolated component can be a part of a pharmaceutical composition that comprises additional pharmaceutically acceptable carriers and/or excipients.
  • nucleic acids or proteins are “isolated” when such nucleic acids or proteins are free of at least some of the cellular components with which it is associated in the natural state, or that the nucleic acid or protein has been concentrated to a level greater than the concentration of its in vivo or in vitro production.
  • a gene is isolated when separated from open reading frames which flank the gene and encode a protein other than the gene of interest.
  • module means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target.
  • a modulator refers to a compound that alters an activity of a molecule.
  • a modulator can cause an increase or decrease in the magnitude of a certain activity of a molecule compared to the magnitude of the activity in the absence of the modulator.
  • a modulator is an inhibitor, which decreases the magnitude of one or more activities of a molecule.
  • an inhibitor completely prevents one or more activities of a molecule.
  • a modulator is an activator, which increases the magnitude of at least one activity of a molecule.
  • the presence of a modulator results in an activity that does not occur in the absence of the modulator.
  • prophylactically effective amount refers that amount of a composition applied to a patient which will relieve to some extent one or more of the symptoms of a disease, condition or disorder being treated. In such prophylactic applications, such amounts may depend on the patient's state of health, weight, and the like. It is considered well within the skill of the art for one to determine such prophylactically effective amounts by routine experimentation, including, but not limited to, a dose escalation clinical trial.
  • subject refers to an animal which is the object of treatment, observation or experiment.
  • a subject may be, but is not limited to, a mammal including, but not limited to, a human.
  • target activity refers to a biological activity capable of being modulated by a selective modulator.
  • Certain exemplary target activities include, but are not limited to, binding affinity, signal transduction, enzymatic activity, tumor growth, inflammation or inflammation-related processes, and amelioration of one or more symptoms associated with a disease or condition.
  • target protein refers to a molecule or a portion of a protein capable of being bound by a selective binding compound.
  • a target protein is Btk.
  • treat include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition.
  • the terms “treat,” “treating” or “treatment”, include, but are not limited to, prophylactic and/or therapeutic treatments.
  • the IC 50 refers to an amount, concentration or dosage of a particular test compound that achieves a 50% inhibition of a maximal response, such as inhibition of Btk, in an assay that measures such response.
  • EC 50 refers to a dosage, concentration or amount of a particular test compound that elicits a dose-dependent response at 50% of maximal expression of a particular response that is induced, provoked or potentiated by the particular test compound.
  • compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers including excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used
  • a pharmaceutical composition or pharmaceutical formulation refers to a mixture of solvated Compound 1 with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
  • the pharmaceutical composition facilitates administration of the compound to a mammal.
  • therapeutically effective amounts of Compound 1 are administered in a pharmaceutical composition to a mammal having a disease, disorder, or condition to be treated.
  • the mammal is a human.
  • a therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors.
  • the compounds can be used singly or in combination with one or more therapeutic agents as components of mixtures.
  • the solvates of Compound 1 described herein can be administered in the pharmaceutical compositions described in U.S. Patent 7,514,444.
  • pharmaceutical combination means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
  • fixed combination means that the active ingredients, e.g. solvated Compound 1 and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • non-fixed combination means that the active ingredients, e.g. solvated Compound 1 and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • combination means that the active ingredients, e.g. solvated Compound 1 and a co-agent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient.
  • active ingredients e.g. solvated Compound 1 and a co-agent
  • cocktail therapy e.g. the administration of three or more active ingredients.
  • the solvates of Compound 1 described herein can be administered in the pharmaceutical combinations described in U.S. Patent 7,514,444.
  • a solvate of Compound 1 is incorporated into
  • compositions to provide solid oral dosage forms In other embodiments, a solvate of Compound 1 is used to prepare pharmaceutical compositions other than solid oral dosage forms.
  • the pharmaceutical formulations described herein can be administered to a subject by multiple administration routes, including but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration routes.
  • the pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, delayed release
  • the pharmaceutical composition comprising a pharmaceutically acceptable carrier and a solvate provided herein is in a solid form or a suspension in a liquid excipient.
  • the pharmaceutical composition is in a liquid solution form and comprises a pharmaceutically acceptable carrier and is prepared from a solvate provided herein.
  • compositions including a compound described herein may be manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.
  • compositions described herein can be formulated for administration to a mammal via any conventional means including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, or intramuscular), buccal, intranasal, rectal or transdermal administration routes.
  • parenteral e.g., intravenous, subcutaneous, or intramuscular
  • buccal e.g., intranasal
  • rectal e.g., transdermal administration routes.
  • transdermal administration routes e.g., transdermal administration routes.
  • subject is used to mean an animal, preferably a mammal, including a human or non-human.
  • patient and subject may be used interchangeably.
  • compositions described herein, which include a solvate of Compound 1 can be formulated into any suitable dosage form, including but not limited to, solid oral dosage forms, controlled release formulations, fast melt formulations, effervescent formulations, tablets, powders, pills, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate release and controlled release formulations.
  • compositions for oral use can be obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium
  • carboxymethylcellulose or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate.
  • PVP polyvinylpyrrolidone
  • disintegrating agents may be added, such as the cross-linked
  • croscarmellose sodium polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • compositions which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
  • the solid dosage forms disclosed herein may be in the form of a tablet, (including a suspension tablet, a fast-melt tablet, a bite-disintegration tablet, a rapid-disintegration tablet, an effervescent tablet, or a caplet), a pill, a powder (including a sterile packaged powder, a dispensable powder, or an effervescent powder) a capsule (including both soft or hard capsules, e.g., capsules made from animal-derived gelatin or plant-derived HPMC, or "sprinkle capsules"), solid dispersion, solid solution, bioerodible dosage form, controlled release formulations, pulsatile release dosage forms, multiparticulate dosage forms, pellets, granules, or an aerosol.
  • a tablet including a suspension tablet, a fast-melt tablet, a bite-disintegration tablet, a rapid-disintegration tablet, an effervescent tablet, or a caplet
  • a pill including a sterile
  • the pharmaceutical formulation is in the form of a powder. In still other embodiments, the pharmaceutical formulation is in the form of a tablet, including but not limited to, a fast-melt tablet. Additionally, pharmaceutical formulations described herein may be administered as a single capsule or in multiple capsule dosage form. In some embodiments, the pharmaceutical formulation is administered in two, or three, or four, capsules or tablets.
  • solid dosage forms e.g., tablets, effervescent tablets, and capsules
  • solid dosage forms are prepared by mixing particles of a solvate of Compound 1 with one or more pharmaceutical excipients to form a bulk blend composition.
  • these bulk blend compositions as homogeneous, it is meant that the particles of a solvate of Compound 1 are dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules.
  • the individual unit dosages may also include film coatings, which disintegrate upon oral ingestion or upon contact with diluent. These formulations can be manufactured by conventional pharmacological techniques.
  • Conventional pharmacological techniques include, e.g., one or a combination of methods: (1) dry mixing, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6) fusion. See, e.g., Lachman et al., The Theory and Practice of
  • the pharmaceutical solid dosage forms described herein can include a solvate of Compound 1 and one or more pharmaceutically acceptable additives such as a compatible carrier, binder, filling agent, suspending agent, flavoring agent, sweetening agent, disintegrating agent, dispersing agent, surfactant, lubricant, colorant, diluent, solubilizer, moistening agent, plasticizer, stabilizer, penetration enhancer, wetting agent, anti-foaming agent, antioxidant, preservative, or one or more combination thereof.
  • a compatible carrier such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000), a film coating is provided around the formulation of a solvate of Compound 1.
  • some or all of the particles of the solvate of Compound 1 are coated. In another embodiment, some or all of the particles of the solvate of Compound 1 are microencapsulated. In still another embodiment, the particles of the solvate of Compound 1 are not
  • Suitable carriers for use in the solid dosage forms described herein include, but are not limited to, acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerine, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglyceride, diglyceride, pregelatinized starch, hydroxypropylmethylcellulose,
  • hydroxypropylmethylcellulose acetate stearate sucrose, microcrystalline cellulose, lactose, mannitol and the like.
  • Suitable filling agents for use in the solid dosage forms described herein include, but are not limited to, lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starches, pregelatinized starch, hydroxypropylmethycellulose (HPMC),
  • HPLC HPLC
  • sucrose sucrose
  • xylitol lactitol
  • mannitol sorbitol
  • sodium chloride polyethylene glycol, and the like.
  • disintegrants are often used in the formulation, especially when the dosage forms are compressed with binder. Disintegrants help rupturing the dosage form matrix by swelling or capillary action when moisture is absorbed into the dosage form.
  • Suitable disintegrants for use in the solid dosage forms described herein include, but are not limited to, natural starch such as corn starch or potato starch, a pregelatinized starch such as National 1551 or Amijel ® , or sodium starch glycolate such as Promogel ® or Explotab ® , a cellulose such as a wood product, methylcrystalline cellulose, e.g., Avicel ® , Avicel ® PH101, Avicel ® PH102, Avicel ® PH105, Elcema ® PI 00, Emcocel ® , Vivacel ® , Ming Tia ® , and Solka-Floc ® , methylcellulose,
  • croscarmellose or a cross-linked cellulose, such as cross-linked sodium carboxymethylcellulose (Ac-Di-Sol ® ), cross-linked carboxymethylcellulose, or cross-linked croscarmellose, a cross- linked starch such as sodium starch glycolate, a cross-linked polymer such as crospovidone, a cross-linked polyvinylpyrrolidone, alginate such as alginic acid or a salt of alginic acid such as sodium alginate, a clay such as Veegum ® HV (magnesium aluminum silicate), a gum such as agar, guar, locust bean, Karaya, pectin, or tragacanth, sodium starch glycolate, bentonite, a natural sponge, a surfactant, a resin such as a cation-exchange resin, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combination starch, and the like.
  • the disintegrating agent is selected from the group consisting of natural starch, a pregelatinized starch, a sodium starch, methylcrystalline cellulose, methylcellulose, croscarmellose, croscarmellose sodium, cross-linked sodium carboxymethylcellulose, cross- linked carboxymethylcellulose, cross-linked croscarmellose, cross-linked starch such as sodium starch glycolate, cross-linked polymer such as crospovidone, cross-linked polyvinylpyrrolidone, sodium alginate, a clay, or a gum.
  • the disintegrating agent is croscarmellose sodium.
  • Binders impart cohesiveness to solid oral dosage form formulations: for powder filled capsule formulation, they aid in plug formation that can be filled into soft or hard shell capsules and for tablet formulation, they ensure the tablet remaining intact after compression and help assure blend uniformity prior to a compression or fill step.
  • Materials suitable for use as binders in the solid dosage forms described herein include, but are not limited to,
  • carboxymethylcellulose methylcellulose (e.g., Methocel ® ), hydroxypropylmethylcellulose (e.g. Hypromellose USP Pharmacoat-603, hydroxypropylmethylcellulose acetate stearate (Aqoate HS-LF and HS), hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel ® ), ethylcellulose (e.g., Ethocel ® ), and microcrystalline cellulose (e.g., Avicel ® ), microcrystalline dextrose, amylose, magnesium aluminum silicate, polysaccharide acids, bentonites, gelatin,
  • polyvinylpyrrolidone/vinyl acetate copolymer crospovidone, povidone, starch, pregelatinized starch, tragacanth, dextrin, a sugar, such as sucrose (e.g., Dipac ® ), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab ® ), lactose, a natural or synthetic gum such as acacia, tragacanth, ghatti gum, mucilage of isapol husks, starch, polyvinylpyrrolidone (e.g., Povidone ® CL, Kollidon ® CL, Polyplasdone ® XL- 10, and Povidone ® K-12), larch arabogalactan, Veegum ® , polyethylene glycol, waxes, sodium alginate, and the like.
  • sucrose
  • binder levels of 20-70% are used in powder-filled gelatin capsule formulations. Binder usage level in tablet formulations varies whether direct compression, wet granulation, roller compaction, or usage of other excipients such as fillers which itself can act as moderate binder. Formulators skilled in art can determine the binder level for the formulations, but binder usage level of up to 70% in tablet formulations is common.
  • Suitable lubricants or glidants for use in the solid dosage forms described herein include, but are not limited to, stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumerate, alkali-metal and alkaline earth metal salts, such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearates, magnesium stearate, zinc stearate, waxes, Stearowet ® , boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a polyethylene glycol or a methoxypolyethylene glycol such as CarbowaxTM, PEG 4000, PEG 5000, PEG 6000, propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate, magnesium or sodium lauryl sulfate, and the like.
  • stearic acid calcium hydroxide, talc
  • the lubricant is selected from the group consisting of stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumerate, stearic acid, sodium stearates, magnesium stearate, zinc stearate, and waxes. In some embodiments provided herein, the lubricant is magnesium stearate.
  • Suitable diluents for use in the solid dosage forms described herein include, but are not limited to, sugars (including lactose, sucrose, and dextrose), polysaccharides (including dextrates and maltodextrin), polyols (including mannitol, xylitol, and sorbitol), cyclodextrins and the like.
  • the diluent is selected from the group consisting of lactose, sucrose, dextrose, dextrates, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrins, calcium phosphate, calcium sulfate, starches, modified starches, microcrystalline cellulose, microcellulose, and talc. In some embodiments provided herein, the diluent is microcrystalline cellulose.
  • non water-soluble diluent represents compounds typically used in the formulation of pharmaceuticals, such as calcium phosphate, calcium sulfate, starches, modified starches and microcrystalline cellulose, and microcellulose (e.g., having a density of about 0.45 g/cm 3 , e.g. Avicel, powdered cellulose), and talc.
  • Suitable wetting agents for use in the solid dosage forms described herein include, for example, oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, quaternary ammonium compounds (e.g., Polyquat 10 ® ), sodium oleate, sodium lauryl sulfate, magnesium stearate, sodium docusate, triacetin, vitamin E TPGS and the like.
  • quaternary ammonium compounds e.g., Polyquat 10 ®
  • sodium oleate sodium lauryl sulfate
  • magnesium stearate sodium docusate
  • triacetin vitamin E TPGS and the like.
  • Suitable surfactants for use in the solid dosage forms described herein include, for example, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, e.g., Pluronic ® (BASF), and the like.
  • the surfactant is selected from the group consisting of sodium lauryl sulfate, sorbitan
  • the surfactant is sodium lauryl sulfate.
  • Suitable suspending agents for use in the solid dosage forms described here include, but are not limited to, polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30,
  • polyethylene glycol e.g., the polyethylene glycol can have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400, vinyl pyrrolidone/vinyl acetate copolymer (S630), sodium carboxymethylcellulose, methylcellulose, hydroxy - propylmethylcellulose, polysorbate-80, hydroxyethylcellulose, sodium alginate, gums, such as, e.g., gum tragacanth and gum acacia, guar gum, xanthans, including xanthan gum, sugars, cellulosics, such as, e.g., sodium carboxymethylcellulose, methylcellulose, sodium
  • carboxymethylcellulose hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone and the like.
  • Suitable antioxidants for use in the solid dosage forms described herein include, for example, e.g., butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol.
  • BHT butylated hydroxytoluene
  • sodium ascorbate sodium ascorbate
  • tocopherol sodium ascorbate
  • additives used in the solid dosage forms described herein there is considerable overlap between additives used in the solid dosage forms described herein.
  • the above-listed additives should be taken as merely exemplary, and not limiting, of the types of additives that can be included in solid dosage forms described herein.
  • the amounts of such additives can be readily determined by one skilled in the art, according to the particular properties desired.
  • one or more layers of the pharmaceutical formulation are plasticized.
  • a plasticizer is generally a high boiling point solid or liquid. Suitable plasticizers can be added from about 0.01% to about 50% by weight (w/w) of the coating composition. Plasticizers include, but are not limited to, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol,
  • polyethylene glycol triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate, and castor oil.
  • Compressed tablets are solid dosage forms prepared by compacting the bulk blend of the formulations described above.
  • compressed tablets which are designed to dissolve in the mouth will include one or more flavoring agents.
  • the compressed tablets will include a film surrounding the final compressed tablet.
  • the film coating can provide a delayed release of a solvate of Compound 1 from the formulation.
  • the film coating aids in patient compliance (e.g., Opadry ® coatings or sugar coating). Film coatings including Opadry ® typically range from about 1% to about 3% of the tablet weight.
  • the compressed tablets include one or more excipients.
  • a capsule may be prepared, for example, by placing the bulk blend of the formulation of solvated Compound 1 inside of a capsule.
  • the formulation of solvated Compound 1 may be prepared, for example, by placing the bulk blend of the formulation of solvated Compound 1 inside of a capsule.
  • formulations are placed in a soft gelatin capsule.
  • the formulations are placed in standard gelatin capsules or non-gelatin capsules such as capsules comprising HPMC.
  • the formulation is placed in a sprinkle capsule, wherein the capsule may be swallowed whole or the capsule may be opened and the contents sprinkled on food prior to eating.
  • the therapeutic dose is split into multiple (e.g., two, three, or four) capsules.
  • the entire dose of the formulation is delivered in a capsule form.
  • the particles of a solvate of Compound 1 and one or more excipients are dry blended and compressed into a mass, such as a tablet, having a hardness sufficient to provide a pharmaceutical composition that substantially disintegrates within less than about 30 minutes, less than about 35 minutes, less than about 40 minutes, less than about 45 minutes, less than about 50 minutes, less than about 55 minutes, or less than about 60 minutes, after oral administration, thereby releasing the formulation into the gastrointestinal fluid.
  • dosage forms may include microencapsulated formulations.
  • one or more other compatible materials are present in the formulations.
  • microencapsulation material examples include, but are not limited to, pH modifiers, erosion facilitators, anti-foaming agents, antioxidants, flavoring agents, and carrier materials such as binders, suspending agents, disintegration agents, filling agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, and diluents.
  • Materials useful for the microencapsulation described herein include materials compatible with a solvate of Compound 1 which sufficiently isolate the solvated Compound 1 from other non-compatible excipients.
  • Materials compatible with a solvate of Compound 1 are those that delay the release of the compounds of solvated Compound 1 in vivo.
  • microencapsulation materials useful for delaying the release of the formulations including compounds described herein include, but are not limited to,
  • HPC hydroxypropyl cellulose ethers
  • L-HPC low- substituted hydroxypropyl cellulose ethers
  • HPMC hydroxypropyl methyl cellulose ethers
  • Seppifilm-LC Pharmacoat ® , Metolose SR, Methocel ® -E, Opadry YS, PrimaFlo, Benecel MP824, and Benecel MP843, methylcellulose polymers such as Methocel ® -A,
  • hydroxypropylmethylcellulose acetate stearate Aqoat HF-LS, HF-LG,HF-MS
  • Metolose ® Ethylcelluloses (EC) and mixtures thereof such as E461, Ethocel ® , Aqualon ® -EC, Surelease ® , Polyvinyl alcohol (PVA) such as Opadry AMB, hydroxyethylcelluloses such as Natrosol ® , carboxymethylcelluloses and salts of carboxymethylcelluloses (CMC) such as Aqualon ® -CMC, polyvinyl alcohol and polyethylene glycol co-polymers such as Kollicoat IR ® , monoglycerides (Myverol), triglycerides (KLX), polyethylene glycols, modified food starch, acrylic polymers and mixtures of acrylic polymers with cellulose ethers such as Eudragit ® EPO, Eudragit ® L30D- 55, Eudragit ® FS 30D Eudragit ®
  • microencapsulation material 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800, stearic acid, propylene glycol, oleic acid, and triacetin are incorporated into the microencapsulation material.
  • compositions is from the USP or the National Formulary (NF).
  • the microencapsulation material is Klucel.
  • the microencapsulation material is methocel.
  • Microencapsulated solvated Compound 1 may be formulated by methods known by one of ordinary skill in the art. Such known methods include, e.g., spray drying processes, spinning disk-solvent processes, hot melt processes, spray chilling methods, fluidized bed, electrostatic deposition, centrifugal extrusion, rotational suspension separation, polymerization at liquid-gas or solid-gas interface, pressure extrusion, or spraying solvent extraction bath. In addition to these, several chemical techniques, e.g., complex coacervation, solvent evaporation, polymer-polymer incompatibility, interfacial polymerization in liquid media, in situ
  • roller compaction extrusion/spheronization, coacervation, or nanoparticle coating may also be used.
  • the particles of a solvate of Compound 1 are
  • microencapsulated prior to being formulated into one of the above forms.
  • some or most of the particles are coated prior to being further formulated by using standard coating procedures, such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000).
  • the solid dosage formulations of solvated Compound 1 are plasticized (coated) with one or more layers.
  • a plasticizer is generally a high boiling point solid or liquid. Suitable plasticizers can be added from about 0.01% to about 50% by weight (w/w) of the coating composition.
  • Plasticizers include, but are not limited to, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate, and castor oil.
  • a powder including the formulations with a solvate of
  • Compound 1 may be formulated to include one or more pharmaceutical excipients and flavors.
  • a powder may be prepared, for example, by mixing the formulation and optional pharmaceutical excipients to form a bulk blend composition. Additional embodiments also include a suspending agent and/or a wetting agent. This bulk blend is uniformly subdivided into unit dosage packaging or multi-dosage packaging units.
  • effervescent powders are also prepared in accordance with the present disclosure. Effervescent salts have been used to disperse medicines in water for oral administration. Effervescent salts are granules or coarse powders containing a medicinal agent in a dry mixture, usually composed of sodium bicarbonate, citric acid and/or tartaric acid.
  • effervescent salts include, e.g., the following ingredients: sodium bicarbonate or a mixture of sodium bicarbonate and sodium carbonate, citric acid and/or tartaric acid. Any acid-base combination that results in the liberation of carbon dioxide can be used in place of the combination of sodium bicarbonate and citric and tartaric acids, as long as the ingredients were suitable for pharmaceutical use and result in a pH of about 6.0 or higher.
  • the solid dosage forms described herein can be formulated as enteric coated delayed release oral dosage forms, i.e., as an oral dosage form of a
  • the enteric coated dosage form may be a compressed or molded or extruded tablet/mold (coated or uncoated) containing granules, powder, pellets, beads or particles of the active ingredient and/or other composition components, which are themselves coated or uncoated.
  • the enteric coated oral dosage form may also be a capsule (coated or uncoated) containing pellets, beads or granules of the solid carrier or the composition, which are themselves coated or uncoated.
  • delayed release refers to the delivery so that the release can be accomplished at some generally predictable location in the intestinal tract more distal to that which would have been accomplished if there had been no delayed release alterations.
  • the method for delay of release is coating. Any coatings should be applied to a sufficient thickness such that the entire coating does not dissolve in the gastrointestinal fluids at pH below about 5, but does dissolve at pH about 5 and above. It is expected that any anionic polymer exhibiting a pH-dependent solubility profile can be used as an enteric coating in the methods and compositions described herein to achieve delivery to the lower gastrointestinal tract.
  • the polymers described herein are anionic carboxylic polymers.
  • the polymers and compatible mixtures thereof, and some of their properties include, but are not limited to:
  • Shellac also called purified lac, a refined product obtained from the resinous secretion of an insect. This coating dissolves in media of pH >7;
  • Acrylic polymers The performance of acrylic polymers (primarily their solubility in biological fluids) can vary based on the degree and type of substitution. Examples of suitable acrylic polymers include methacrylic acid copolymers and ammonium methacrylate copolymers.
  • the Eudragit series E, L, S, RL, RS and NE are available as solubilized in organic solvent, aqueous dispersion, or dry powders.
  • the Eudragit series RL, NE, and RS are insoluble in the gastrointestinal tract but are permeable and are used primarily for colonic targeting.
  • the Eudragit series E dissolve in the stomach.
  • the Eudragit series L, L-30D and S are insoluble in stomach and dissolve in the intestine;
  • Cellulose Derivatives are: ethyl cellulose; reaction mixtures of partial acetate esters of cellulose with phthalic anhydride. The performance can vary based on the degree and type of substitution.
  • Cellulose acetate phthalate (CAP) dissolves in pH >6.
  • Aquateric (FMC) is an aqueous based system and is a spray dried CAP psuedolatex with particles ⁇ 1 ⁇ .
  • Other components in Aquateric can include pluronics, Tweens, and acetylated monoglycerides.
  • Suitable cellulose derivatives include: cellulose acetate trimellitate (Eastman); methylcellulose (Pharmacoat, Methocel); hydroxypropylmethyl cellulose phthalate (HPMCP); hydroxypropylmethyl cellulose succinate (HPMCS); and hydroxypropylmethylcellulose acetate succinate (e.g., AQOAT (Shin Etsu)).
  • HPMCS hydroxypropylmethyl cellulose succinate
  • AQOAT Shin Etsu
  • the performance can vary based on the degree and type of substitution.
  • FIPMCP such as, FIP-50, FIP-55, HP-55S, FIP-55F grades are suitable.
  • the performance can vary based on the degree and type of substitution.
  • suitable grades of hydroxypropylmethylcellulose acetate succinate include, but are not limited to, AS-LG (LF), which dissolves at pH 5, AS-MG (MF), which dissolves at pH 5.5, and AS-HG (ELF), which dissolves at higher pH.
  • AS-LG LF
  • AS-MG MF
  • AS-HG ELF
  • PVAP Poly Vinyl Acetate Phthalate
  • the coating can, and usually does, contain a plasticizer and possibly other coating excipients such as colorants, talc, and/or magnesium stearate, which are well known in the art.
  • Suitable plasticizers include triethyl citrate (Citroflex 2), triacetin
  • anionic carboxylic acrylic polymers usually will contain 10-25% by weight of a plasticizer, especially dibutyl phthalate,
  • polyethylene glycol, triethyl citrate and triacetin polyethylene glycol, triethyl citrate and triacetin.
  • Conventional coating techniques such as spray or pan coating are employed to apply coatings.
  • the coating thickness must be sufficient to ensure that the oral dosage form remains intact until the desired site of topical delivery in the intestinal tract is reached.
  • Colorants, detackifiers, surfactants, antifoaming agents, lubricants e.g., carnuba wax or PEG may be added to the coatings besides plasticizers to solubilize or disperse the coating material, and to improve coating performance and the coated product.
  • the formulations described herein, which include solvates of Compound 1 are delivered using a pulsatile dosage form.
  • a pulsatile dosage form is capable of providing one or more immediate release pulses at predetermined time points after a controlled lag time or at specific sites.
  • Examples of such delivery systems include, e.g., polymer-based systems, such as polylactic and polyglycolic acid, plyanhydrides and polycaprolactone; porous matrices, nonpolymer-based systems that are lipids, including sterols, such as cholesterol, cholesterol esters and fatty acids, or neutral fats, such as mono-, di- and triglycerides; hydrogel release systems; silastic systems; peptide-based systems; wax coatings, bioerodible dosage forms, compressed tablets using conventional binders and the like. See, e.g., Liberman et al., Pharmaceutical Dosage Forms, 2 Ed., Vol. 1, pp.
  • compositions that include particles of a solvate of Compound 1 and at least one dispersing agent or suspending agent for oral administration to a subject.
  • the formulations may be a powder and/or granules for suspension, and upon admixture with water, a substantially uniform suspension is obtained.
  • a solvate of Compound 1 is administered to a mammal in an amount that delivers Compound 1 to the mammal in an amount as described herein.
  • the amount of Compound 1 is from 300 mg/day up to, and including, 1000 mg/day.
  • the amount of a solvate of Compound 1 that is administered to a mammal is from 420 mg/day up to, and including, 840 mg/day.
  • the amount of a solvate of Compound 1 that is administered to a mammal delivers Compound 1 in an amount of about 420 mg/day, about 560 mg/day, or about 840 mg/day.
  • the amount of Compound 1 is about 420 mg/day. In some embodiments, the amount of Compound 1 is about 560 mg/day. In some embodiments, the AUC 0- 24 of Compound 1 is between about 150 and about 3500 ng*h/mL. In some embodiments, the AUCo-24 of Compound 1 is between about 500 and about 1100 ng*h/mL. In some embodiments, a solvate of Compound 1 is administered orally. In some embodiments, a solvate of Compound 1 is administered once per day, twice per day, or three times per day. In some embodiments, a solvate of Compound 1 is administered daily. In some embodiments, a solvate of Compound 1 is administered once daily. In some embodiments, a solvate of Compound 1 is administered every other day. In some embodiments, a solvate of Compound 1 is a maintenance therapy.
  • a solvate of Compound 1 can be used in the preparation of medicaments for the inhibition of Btk or a homolog thereof, or for the treatment of diseases or conditions that would benefit, at least in part, from inhibition of Btk or a homolog thereof, including a subject diagnosed with a hematological malignancy.
  • a method for treating any of the diseases or conditions described herein in a subject in need of such treatment involves administration of pharmaceutical compositions containing a solvate of Compound 1, or a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said subject.
  • compositions containing a solvate of Compound 1 can be administered for prophylactic, therapeutic, or maintenance treatment.
  • compositions containing a solvate of Compound 1 are administered for therapeutic applications (e.g., administered to a subject diagnosed with a hematological malignancy).
  • compositions containing a solvate of Compound 1 are administered for prophylactic applications (e.g., administered to a subject susceptible to or otherwise at risk of developing a hematological malignancy).
  • compositions containing a solvate of Compound 1 are administered to a patient who is in remission as a maintenance therapy.
  • Amounts of solvated Compound 1 will depend on the use (e.g., therapeutic, prophylactic, or maintnenace). Amounts of a solvate of Compound 1 will depend on severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician. It is considered well within the skill of the art for one to determine such therapeutically effective amounts by routine
  • the amount of a solvate of Compound 1 provides Compound 1 from 300 mg/day up to, and including, 1000 mg/day. In some embodiments, the amount of Compound 1 is from 420 mg/day up to, and including, 840 mg/day. In some embodiments, the amount of Compound 1 is from 400 mg/day up to, and including, 860 mg/day. In some embodiments, the amount of Compound 1 is about 360 mg/day. In some embodiments, the amount of Compound 1 is about 420 mg/day. In some embodiments, the amount of Compound 1 is about 560 mg/day. In some embodiments, the amount of Compound 1 is about 840 mg/day. In some embodiments, the amount of Compound 1 is from 2 mg/kg/day up to, and including, 13 mg/kg/day. In some embodiments, the amount of Compound 1 is from 2.5 mg/kg/day up to, and including,
  • the amount of Compound 1 is from 2.5 mg/kg/day up to, and including, 6 mg/kg/day. In some embodiments, the amount of Compound 1 is from
  • Compound 1 is about 2.5 mg/kg/day. In some embodiments, the amount of Compound 1 is about 8 mg/kg/day.
  • compositions decribed herein include about 140 mg of Compound 1.
  • a capsule formulation is prepared that includes about 140 mg of Compound 1.
  • 2, 3, 4, or 5 of the capsule formulations are administered daily.
  • 3 or 4 of the capsules are
  • the capsules are administered daily. In some embodiments, 3 of the 140 mg capsules are administered once daily. In some embodiments, 4 of the 140 mg capsules are administered once daily. In some embodiments, the capsules are administered once daily. In other embodiments, the capsules are administered multiple times a day.
  • a solvate of Compound 1 is administered daily. In some embodiments, a solvate of Compound 1 is administered every other day.
  • a solvate of Compound 1 is administered once per day. In some embodiments, a solvate of Compound 1 is administered twice per day. In some
  • a solvate of Compound 1 is administered three times per day.
  • a solvate of Compound 1 is administered four times per per day.
  • a solvate of Compound 1 is administered until disease progression, unacceptable toxicity, or individual choice. In some embodiments, a solvate of
  • Compound 1 is administered daily until disease progression, unacceptable toxicity, or individual choice. In some embodiments, a solvate of Compound 1 is administered every other day until disease progression, unacceptable toxicity, or individual choice.
  • the administration of the compounds may be given continuously; alternatively, the dose of drug being administered may be temporarily reduced or temporarily suspended for a certain length of time (i.e., a "drug holiday").
  • the length of the drug holiday can vary between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days.
  • the dose reduction during a drug holiday may be from 10%- 100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.
  • a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. Patients can, however, require intermittent treatment on a long- term basis upon any recurrence of symptoms.
  • the amount of a given agent that will correspond to such an amount will vary depending upon factors such as the particular compound, the severity of the disease, the identity (e.g., weight) of the subject or host in need of treatment, but can nevertheless be routinely determined in a manner known in the art according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, and the subject or host being treated.
  • doses employed for adult human treatment will typically be in the range of 0.02-5000 mg per day, or from about 1-1500 mg per day.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses per day.
  • the pharmaceutical composition described herein may be in unit dosage forms suitable for single administration of precise dosages.
  • the formulation is divided into unit doses containing appropriate quantities of one or more compound.
  • the unit dosage may be in the form of a package containing discrete quantities of the formulation.
  • Non- limiting examples are packaged tablets or capsules, and powders in vials or ampoules.
  • Aqueous suspension compositions can be packaged in single-dose non-reclosable containers.
  • each unit dosage form comprises 140 mg of Compound 1.
  • an individual is administerd 1 unit dosage form per day.
  • an individual is administerd 2 unit dosage forms per day.
  • an individual is administerd 3 unit dosage forms per day.
  • an individual is administerd 4 unit dosage forms per day.
  • Toxicity and therapeutic efficacy of such therapeutic regimens can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between the toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD 50 and ED 50 .
  • Compounds exhibiting high therapeutic indices are preferred.
  • the data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in human.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 50 with minimal toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • compositions and methods described herein are also used in conjunction with other therapeutic reagents that are selected for their particular usefulness against the condition that is being treated.
  • compositions described herein and, in embodiments where combinational therapy is employed other agents do not have to be administered in the same pharmaceutical composition, and are, because of different physical and chemical characteristics, administered by different routes.
  • the initial administration is made according to established protocols, and then, based upon the observed effects, the dosage, modes of administration and times of administration, further modified.
  • the compounds are administered concurrently (e.g., simultaneously, essentially simultaneously or within the same treatment protocol) or
  • the determination of the order of administration, and the number of repetitions of administration of each therapeutic agent during a treatment protocol is based upon evaluation of the disease being treated and the condition of the patient.
  • dosages of the co-administered compounds vary depending on the type of co-drug employed, on the specific drug employed, on the disease or condition being treated and so forth.
  • the individual compounds of such combinations are administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.
  • the individual compounds will be administered simultaneously in a combined pharmaceutical formulation.
  • Appropriate doses of known therapeutic agents will be appreciated by those skilled in the art.
  • a method for treating a cancer in an individual in need thereof comprising: administering to the individual an amount of a solvate of Compound 1.
  • the method further comprises administering a second cancer treatment regimen.
  • administering a Btk inhibitor before a second cancer treatment regimen reduces immune-mediated reactions to the second cancer treatment regimen.
  • administering a solvate of Compound 1 before ofatumumab reduces immune-mediated reactions to ofatumumab.
  • the second cancer treatment regimen comprises a chemotherapeutic agent, a steroid, an immunotherapeutic agent, a targeted therapy, or a combination thereof.
  • the second cancer treatment regimen comprises a B cell receptor pathway inhibitor.
  • the B cell receptor pathway inhibitor is a CD79A inhibitor, a CD79B inhibitor, a CD 19 inhibitor, a Lyn inhibitor, a Syk inhibitor, a PI3K inhibitor, a Blnk inhibitor, a PLCy inhibitor, a PKCP inhibitor, a LYN inhibitor, a JAK inhibitor, a MAPK inhibitor, a MEK inhibitor or a NFKB inhibitor or a combination thereof.
  • the second cancer treatment regimen comprises an antibody, B cell receptor signaling inhibitor, a PI3K inhibitor, an IAP inhibitor, an mTOR inhibitor, a
  • radioimmunotherapeutic a DNA damaging agent, a proteosome inhibitor, a Cyp3 A4 inhibitor, a histone deacetylase inhibitor, a protein kinase inhibitor, a hedgehog inhibitor, an Hsp90 inhibitor, a telomerase inhibitor, a Jakl/2 inhibitor, a protease inhibitor, a PKC inhibitor, a PARP inhibitor, or a combination thereof.
  • the second cancer treatment regimen comprises chlorambucil, ifosphamide, doxorubicin, mesalazine, thalidomide, lenalidomide, temsirolimus, everolimus, fludarabine, fostamatinib, paclitaxel, docetaxel, ofatumumab, rituximab,
  • dexamethasone prednisone, CAL-101, ibritumomab, tositumomab, bortezomib, pentostatin, endostatin, or a combination thereof.
  • the second cancer treatment regimen comprises cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone, and optionally, rituximab.
  • the second cancer treatment regimen comprises bendamustine, and rituximab.
  • the second cancer treatment regimen comprises fludarabine, cyclophosphamide, and rituximab.
  • the second cancer treatment regimen comprises cyclophosphamide, vincristine, and prednisone, and optionally, rituximab.
  • the second cancer treatment regimen comprises etoposide, doxorubicin, vinristine, cyclophosphamide, prednisolone, and optionally, rituximab.
  • the second cancer treatment regimen comprises dexamethasone and lenalidomide.
  • the second cancer treatment comprises a proteasome inhibitor. In some embodiments, the second treatment comprises bortezomib. In some embodiments, the second cancer treatment comprises an epoxyketone. In some embodiments, the second cancer treatment comprises epoxomicin. In some embodiments, the second cancer treatment comprises a tetrapeptide epoxyketone In some embodiments, the second cancer treatment comprises carfilzomib. In some embodiments, the second cancer treatment comprises disulfram, epigallocatechin-3-gallate, salinosporamide A, ONX 0912m CEP-18770, MLN9708, or MG132.
  • the second cancer treatment comprises a Cyp3 A4 inhibitor.
  • the second cancer treatment comprises indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole, nefazodone.
  • the second cancer treatment comprises ketoconazole.
  • the second cancer treatment comprises a Janus Kinase (JAK) inhibitor. In some embodiments, the second treatment comprises Lestaurtinib,
  • Tofacitinib Ruxolitinib, CYT387, Baricitinib or Pacritinib.
  • the second cancer treatment comprises a histone deacetylase inhibitor (HDAC inhibitor, HDI).
  • HDAC inhibitor histone deacetylase inhibitor
  • the second cancer treatment comprises a hydroxamic acid (or hydroxamate), such as trichostatin A, vorinostat (SAHA), belinostat (PXD101), LAQ824, and panobinostat (LBH589), a cyclic tetrapeptide, such as trapoxin B, a depsipeptide, a benzamide, such as entinostat (MS-275), CI994, and mocetinostat (MGCD0103), an electrophilic ketone, or an aliphatic acid compound, such as phenylbutyrate and valproic acid,
  • Additional cancer treatment regimens include Nitrogen Mustards such as for example, bendamustine, chlorambucil, chlormethine, cyclophosphamide, ifosfamide, melphalan, prednimustine, trofosfamide; Alkyl Sulfonates like busulfan, mannosulfan, treosulfan; Ethylene Imines like carboquone, thiotepa, triaziquone; Nitrosoureas like carmustine, fotemustine, lomustine, nimustine, ranimustine, semustine, streptozocin; Epoxides such as for example, etoglucid; Other Alkylating Agents such as for example dacarbazine, mitobronitol, pipobroman, temozolomide; Folic Acid Analogues such as for example methotrexate, permetrexed, pralatrexate, raltitrexed; Purine Analog
  • Actinomycines such as for example dactinomycin
  • Antracyclines such as for example aclarubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, pirarubicin, valrubicin, zorubincin
  • Other Cytotoxic Antibiotics such as for example bleomycin, ixabepilone, mitomycin, plicamycin
  • Platinum Compounds such as for example carboplatin, cisplatin, oxaliplatin, satraplatin
  • Methylhydrazines such as for example procarbazine
  • Sensitizers such as for example aminolevulinic acid, efaproxiral, methyl aminolevulinate, porfimer sodium, temoporfin
  • Protein Kinase Inhibitors such as for example dasatinib, erlotinib, everolimus, gefitinib,
  • Additional cancer treatment regimens include interferons, interleukins, Tumor
  • Additional cancer treatment regimens include Immunostimulants such as for example ancestim, filgrastim, lenograstim, molgramostim, pegfilgrastim, sargramostim;
  • Interferons such as for example interferon alfa natural, interferon alfa-2a, interferon alfa-2b, interferon alfacon-1, interferon alfa-nl, interferon beta natural, interferon beta- la, interferon beta- lb, interferon gamma, peginterferon alfa-2a, peginterferon alfa-2b; Interleukins such as for example aldesleukin, oprelvekin; Other Immunostimulants such as for example BCG vaccine, glatiramer acetate, histamine dihydrochloride, immunocyanin, lentinan, melanoma vaccine, mifamurtide, pegademase, pidotimod, plerixafor, poly I:C, poly ICLC, roquinimex, tasonermin, thymopentin; Immunosuppressants such as for example abatacept, abetimus
  • Additional cancer treatment regimens include Adalimumab, Alemtuzumab,
  • Basiliximab Bevacizumab, Cetuximab, Certolizumab pegol, Daclizumab, Eculizumab, Efalizumab, Gemtuzumab, Ibritumomab tiuxetan, Infliximab, Muromonab-CD3, Natalizumab, Panitumumab, Ranibizumab, Rituximab, Tositumomab, Trastuzumab, or the like, or a combination thereof.
  • Additional cancer treatment regimens include Monoclonal Antibodies such as for example alemtuzumab, bevacizumab, catumaxomab, cetuximab, edrecolomab, gemtuzumab, ofatumumab, panitumumab, rituximab, trastuzumab, , Immunosuppressants, eculizumab, efalizumab, muromab-CD3, natalizumab; TNF alpha Inhibitors such as for example adalimumab, afelimomab, certolizumab pegol, golimumab, infliximab, , Interleukin Inhibitors, basiliximab, canakinumab, daclizumab, mepolizumab, tocilizumab, ustekinumab, ,
  • Radiopharmaceuticals ibritumomab tiuxetan, tositumomab; Others Monoclonal Antibodies such as for example abagovomab, adecatumumab, alemtuzumab, anti-CD30 monoclonal antibody Xmab2513, anti-MET monoclonal antibody MetMab, apolizumab, apomab, arcitumomab, basiliximab, bispecific antibody 2B1, blinatumomab, brentuximab vedotin, capromab pendetide, cixutumumab, claudiximab, conatumumab, dacetuzumab, denosumab, eculizumab,
  • epratuzumab epratuzumab, epratuzumab, ertumaxomab, etaracizumab, figitumumab, fresolimumab, galiximab, ganitumab, gemtuzumab ozogamicin, glembatumumab, ibritumomab, inotuzumab ozogamicin, ipilimumab, lexatumumab, lintuzumab, lintuzumab, lucatumumab, mapatumumab, matuzumab, milatuzumab, monoclonal antibody CC49, necitumumab, nimotuzumab, ofatumumab, oregovomab, pertuzumab, ramacurimab, ranibizumab, siplizumab, sonepcizumab,
  • Additional cancer treatment regimens include agents that affect the tumor micro- enviroment such as cellular signaling network (e.g. phosphatidylinositol 3-kinase (PI3K) signaling pathway, signaling from the B-cell receptor and the IgE receptor).
  • cellular signaling network e.g. phosphatidylinositol 3-kinase (PI3K) signaling pathway, signaling from the B-cell receptor and the IgE receptor.
  • PI3K phosphatidylinositol 3-kinase
  • the second agent is a PI3K signaling inhibitor or a syc kinase inhibitor.
  • the syk inhibitor is R788.
  • a PKOy inhibitor such as by way of example only, enzastaurin.
  • agents that affect the tumor micro-environment include PI3K signaling inhibitor, syc kinase inhibitor, Protein Kinase Inhibitors such as for example dasatinib, erlotinib, everolimus, gefitinib, imatinib, lapatinib, nilotinib, pazonanib, sorafenib, sunitinib, temsirolimus; Other Angiogenesis Inhibitors such as for example GT-111, JI-101, R1530; Other Kinase Inhibitors such as for example AC220, AC480, ACE-041, AMG 900, AP24534, Arry- 614, AT7519, AT9283, AV-951, axitinib, AZD1152, AZD7762, AZD8055, AZD8931, bafetinib, BAY 73-4506, BGJ398, BGT226, BI 811283,
  • anti-cancer agents for use in combination with a Btk inhibitor compound include inhibitors of mitogen-activated protein kinase signaling, e.g.,
  • anti-cancer agents that can be employed in combination with a Btk inhibitor compound include Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carb
  • carmustine carubicin hydrochloride
  • carzelesin cedefingol
  • chlorambucil cirolemycin
  • cladribine crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin;
  • estramustine estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; cambine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine
  • hydrochloride hydroxyurea; idarubicin hydrochloride; ifosfamide; iimofosine; interleukin II (including recombinant interleukin II, or rlL2), interferon alfa-2a; interferon alfa-2b; interferon alfa-nl; interferon alfa-n3; interferon beta-1 a; interferon gamma-1 b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride;
  • lometrexol sodium lomustine; losoxantrone hydrochloride; masoprocol; maytansine;
  • mechlorethamine hydrochloride megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazoie; nogalamycin; ormaplatin; oxisuran;
  • pegaspargase peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman;
  • piposulfan piroxantrone hydrochloride
  • plicamycin plicamycin
  • plomestane porfimer sodium
  • porfiromycin prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; pumprazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur;
  • teloxantrone hydrochloride temoporfin; teniposide; teroxirone; testolactone; thiamiprine;
  • anti-cancer agents that can be employed in combination with a Btk inhibitor compound include: 20-epi-l, 25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide;
  • anastrozole andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen, prostatic carcinoma; antiestrogen;
  • antineoplaston antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine;
  • azatyrosine baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A;
  • bizelesin breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole;
  • carboxyamidotriazole CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorlns; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole;
  • collismycin A collismycin B; combretastatin A4; combretastatin analogue; conagenin;
  • crambescidin 816 crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A;
  • cyclopentanthraquinones cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;
  • cytostatin cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone;
  • dexifosfamide dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; 9- dioxamycin; diphenyl spiromustine; docosanol; dolasetron;
  • edrecolomab eflornithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane;
  • fadrozole fadrozole; trasrabine; fenretinide; filgrastim; finasteride; fiavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors;
  • gemcitabine glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide;
  • hypericin ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat;
  • imidazoacridones imiquimod
  • immunostimulant peptides insulin-such as for example growth factor-1 receptor inhibitor
  • interferon agonists interferons
  • interleukins interleukins
  • iobenguane interleukins
  • iododoxorubicin ipomeanol, 4-; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin;
  • lenograstim lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds;
  • mitomycin analogues mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotrophin;
  • oligonucleotides onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer;
  • ormaplatin osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol;
  • phenazinomycin phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins;
  • pyrazoloacridine pyridoxylated hemoglobin polyoxyethylerie conjugate; raf antagonists;
  • raltitrexed ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone B l; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen-binding protein; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparf
  • spicamycin D spiromustine; splenopentin; spongistatin 1; squalamine
  • stem cell inhibitor stem- cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur;
  • tellurapyrylium tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide;
  • tetrachlorodecaoxide tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex;
  • urogenital sinus-derived growth inhibitory factor urokinase receptor antagonists
  • vapreotide variolin B
  • vector system erythrocyte gene therapy
  • velaresol veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.
  • nitrogen mustards e.g., mechloroethamine, cyclophosphamide, chlorambucil, etc.
  • alkyl sulfonates e.g., busulfan
  • nitrosoureas e.g., carmustine, lomusitne, ete.
  • triazenes e.g., triazenes
  • antimetabolites include but are not limited to folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., Cytarabine), purine analogs (e.g.,
  • alkylating agents that can be employed in combination a Btk inhibitor compound include, but are not limited to, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, meiphalan, etc.), ethylenimine and methylmelamines (e.g., hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin, etc.), or triazenes (decarbazine, ete.).
  • nitrogen mustards e.g., mechloroethamine, cyclophosphamide, chlorambucil, meiphalan, etc.
  • ethylenimine and methylmelamines e.g., hexamethlymelamine, thiotepa
  • antimetabolites include, but are not limited to folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, floxouridine, Cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin.
  • folic acid analog e.g., methotrexate
  • pyrimidine analogs e.g., fluorouracil, floxouridine, Cytarabine
  • purine analogs e.g., mercaptopurine, thioguanine, pentostatin.
  • Examples of anti-cancer agents which act by arresting cells in the G2-M phases due to stabilized microtubules and which can be used in combination with a Btk inhibitor compound include without limitation the following marketed drugs and drugs in development: Erbulozole (also known as R-55104), Dolastatin 10 (also known as DLS-10 and NSC-376128), Mivobulin isethionate (also known as CI-980), Vincristine, NSC-639829, Discodermolide (also known as NVP-XX-A-296), ABT-751 (Abbott, also known as E-7010), Altorhyrtins (such as Altorhyrtin A and Altorhyrtin C), Spongistatins (such as Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8, and Spongistatin 9), Ce
  • Epothilone A or dEpoA desoxyepothilone A or dEpoA
  • Epothilone D also referred to as KOS-862, dEpoB, and desoxyepothilone B
  • Epothilone E Epothilone F
  • Epothilone B N-oxide Epothilone A N- oxide
  • 16-aza-epothilone B 21-aminoepothilone B (also known as BMS-310705)
  • 21- hydroxyepothilone D also known as Desoxyepothilone F and dEpoF
  • Auristatin PE also known as NSC-654663
  • Soblidotin also known as TZT-1027
  • LS-4559-P Pulacia, also known as LS-4577
  • LS-4578 also known as LS-477-P
  • LS-4477 Pulacia
  • the additional anti-cancer agent that is a Bcl-2 inhibitor.
  • the additional anti-cancer agent is immune checkpoint inhibitor.
  • the immune checkpoint inhibitor is an inhibitor of Programmed Death-Ligand 1 (PD-Ll, also known as B7-Hl, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, 2B4, A2aR, B7H1, B7H3, B7H4, BTLA, CD2, CD27, CD28, CD30, CD40, CD70, CD80, CD86, CD137,CD160, CD226, CD276, DR3, GAL9, GITR, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), KIR, LAIR1, LIGHT, MARCO (macrophage receptor with collageneous structure), PS (phosphatidylserine), OX- 40, SLAM, TIGHT, VISTA, VTCN1, or any combinations
  • PD-Ll also known as B7
  • the immune checkpoint inhibitor is an inhibitor of PD-Ll, PD-1, CTLA-4, LAG3, or TIM3. In some embodiments, the immune checkpoint inhibitor is an inhibitor of PD-Ll . In some embodiments, the immune checkpoint inhibitor is an inhibitor of PD-1. In some embodiments, the immune checkpoint inhibitor is an inhibitor of CTLA-4. In some embodiments, the immune checkpoint inhibitor is an inhibitor of LAG3. In some embodiments, the immune checkpoint inhibitor is an inhibitor of TIM3. In some embodiments, the immune checkpoint inhibitor is an inhibitor of PD- L2.
  • the solvates are administered in combination with a CD20 inhibitor.
  • CD20 inhibitors include, but are not limited to, ibritumomab tiuxetan, ofatumumab, rituximab, tositumomab, and obinutuzumab.
  • the additional anticancer agent used in combination with the solvates described herein include CDK4 inhibitors (e.g., palbociclib).
  • the additional cancer agent is a proteosome inhibitor.
  • the proteasome inhibitor is selected from bortezomib or carfilzomib [00351]
  • the additional cancer agent that can be administered in combination with the solvates is an HDAC inhibitor.
  • the HDAC inhibitor is abexinostat or a salt thereof.
  • the abexinostat or a salt thereof is abexinostat HC1.
  • the abexinostat or a salt thereof is abexinostat tosylate.
  • the additional cancer agent that can be administered in combination with the solvates is a MALTl inhibitor, MCL-1 inhibitor, IDHl inhibitor, TLR inhibitor, or PIM inhibitor.
  • the additional anti-cancer agent that can be administered in combination with the solvates is an immunomodulatory agent.
  • immunomodulatory agents include, but are not limited to, lenalidomide, thalidomide, and pomalidomide.
  • the solvates are administered in combination with an additional agent selected from idelalisib (GS-1101), pentostatine and etopside.
  • the solvates are administered with an additional therapeutic agent comprising the HyperCVAD regimen (cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with methotrexate and cytarabine), FCR regimen (FCR (fludarabine, cyclophosphamide, rituximab), R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), FCMR regimen (fludarabine, cyclophosphamide, mitoxantrone, rituximab), FMR regimen (fludarabine, mitoxantrone, rituximab), PCR regimen (pentostatin, cyclophosphamide, vincristine, doxorubic
  • the solvates may be used with an analgesic such as acetaminophen.
  • the solvates may be used in any combination with one or more other anti- thromboembolic agents to treat or prevent thromboembolic disorder (e.g., stroke).
  • anti-thromboembolic agents include, but are not limited any of the following: thrombolytic agents (e.g., alteplase anistreplase, streptokinase, urokinase, or tissue plasminogen activator), heparin, tinzaparin, warfarin, dabigatran (e.g., dabigatran etexilate), factor Xa inhibitors (e.g., fondaparinux, draparinux, rivaroxaban, DX-9065a, otamixaban, LY517717, or YM150), ticlopidine, clopidogrel, CS-747 (prasugrel, LY640315), ximelagatran, or BIBR 1048.
  • a solvate of Compound 1 can be used in with one or more of the following therapeutic agents in any combination: immunosuppressants (e.g., tacrolimus, cyclosporin, rapamicin, methotrexate, cyclophosphamide, azathioprine, mercaptopurine, mycophenolate, or FTY720), glucocorticoids (e.g., prednisone, cortisone acetate, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclometasone, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone), non-steroidal anti-inflammatory drugs (e.g., salicylates, arylalkanoic acids, 2-arylpropionic acids
  • kits and articles of manufacture are also described herein.
  • Such kits include a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein.
  • Suitable containers include, for example, bottles, vials, syringes, and test tubes.
  • the containers are formed from a variety of materials such as glass or plastic.
  • the articles of manufacture provided herein contain packaging materials.
  • Packaging materials for use in packaging pharmaceutical products include, e.g., U.S. Patent No. 5,323,907 (incorporated by reference).
  • Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, bags, containers, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment.
  • the solvates of Compound 1 or compositions described herein are presented in a package or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
  • the solvate of Compound 1 or composition described herein is packaged alone, or packaged with another compound or another ingredient or additive.
  • the package contains one or more containers filled with one or more of the ingredients of the pharmaceutical compositions.
  • the package comprises metal or plastic foil, such as a blister pack.
  • the package or dispenser device is accompanied by instructions for administration, such as instructions for administering the solvates of Compound 1 or compositions for treating a neoplastic disease.
  • the package or dispenser is accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration.
  • a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration.
  • such notice for example, is the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert.
  • compositions include a solvate of Compound 1 described herein formulated in a compatible pharmaceutical carrier are prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • the container(s) include a solvate of Compound 1, optionally in a composition or in combination with another agent as disclosed herein.
  • kits optionally include an identifying description or label or instructions relating to its use in the methods described herein.
  • a kit typically includes labels listing contents and/or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included.
  • a label is on or associated with the container.
  • a label is on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself; a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert.
  • a label is used to indicate that the contents are to be used for a specific therapeutic application. The label also indicates directions for use of the contents, such as in the methods described herein.
  • the pharmaceutical compositions are presented in a pack or dispenser device which contains one or more unit dosage forms containing a solvate of Compound 1 provided herein.
  • the pack for example, contains metal or plastic foil, such as a blister pack.
  • the pack or dispenser device is accompanied by instructions for administration.
  • the pack or dispenser is also accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, is the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert.
  • compositions containing a compound provided herein formulated in a compatible pharmaceutical carrier are also prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • chlorobenzotrifluoride chloroform, cyclopentylmethyl ether, cyclohexane, cyclohexanone, 1,2- di chlorobenzene, 1,2-dichloroethane, 1,2-dimethoxy ethane, dimethylacetamide, ethylene glycol, glycerol, hexafluorobenzene, dimethyl carbonate, methyl-THF, N-methylpyrrolidone, perfluorohexane, propionitrile, tnfluoroethanol, trifluorotoluene, or xylene] were stirred at 5°C overnight. Vials containing suspensions were filtered and the collected solid was analyzed by XRPD.
  • Compound 1 solvates were obtained: Compound 1 butyronitrile solvate (Form 1), Compound 1 1,2-dimethoxy ethane solvate (Form 2), Compound 1 hexafluorobenzene solvate (Form 4), Compound 1 acetophenone solvate (Form 5), and Compound 1 dimethylacetamide solvate (Form 8).
  • Example 2c Preparation of Crystalline Forms of Compound 1 Solvates - Maturation Method
  • Example 2b The resulting suspension was stirred at 5°C for 10 minutes. The thick suspension was diluted with 1,2-dimethoxy ethane (0.5 mL). The solid was collected by filtration and washed with 1,2-dimethoxy ethane (0.5 mL) to give Compound 1 1,2-dimethoxy ethane solvate (Form 2) (0.6 equivalents of 1,2-dimethoxy ethane).
  • Example 6a Scale-up Preparation of Crystalline Compound 1 Acetophenone Solvate (Form 5)
  • Example 6b Scale-up Preparation of Crystalline Compound 1 Acetophenone Solvate (Form 5)
  • Example 6b (300 mg) in heptane (3 mL) was sonicated at room temperature for 20 minutes. The solid was collected by filtration and washed with heptane (3 mL). The solid was re-suspended in heptane and stirred at room temperature for 72 hours. The solid was collected by filtration to give Compound 1 acetophenone solvate (Form 7) (0.46 equivalent of acetophenone).
  • Amorphous Compound 1 (about 40 mg) was suspended in benzyl acetate
  • X-Ray Powder Diffraction patterns were collected on a Bruker AXS C2 GADDS diffractometer using Cu Ka radiation (40 kV, 40 mA), automated XYZ stage, laser video microscope for auto-sample positioning and a Hi Star 2-dimensional area detector.
  • X-ray optics consists of a single Gobel multilayer mirror coupled with a pinhole collimator of 0.3 mm.
  • a weekly performance check is carried out using a certified standard NIST 1976 Corundum (flat plate). The beam divergence, i.e. the effective size of the X-ray beam on the sample, was approximately 4 mm.
  • a ⁇ - ⁇ continuous scan mode was employed with a sample - detector distance of 20 cm which gives an effective 2 ⁇ range of 3.2 ° - 29.7 °. Typically the sample would be exposed to the X-ray beam for 120 seconds.
  • the software used for data collection was GADDS for XP/2000 4.1.43 and the data were analysed and presented using Diffrac Plus EVA vl5.0.0.0. Ambient conditions
  • Samples run under ambient conditions were prepared as flat plate specimens using powder as received without grinding. Approximately 1-2 mg of the sample was lightly pressed on a glass slide to obtain a flat surface.
  • the X-ray powder diffraction for Compound 1 butyronitrile solvate has the peaks in Table 1 :
  • dimethoxy ethane solvate has the peaks in Table 2:
  • the X-ray powder diffraction for Compound 1 acetophenone solvate has the peaks in Table 5:
  • the X-ray powder diffraction for Compound 1 chlorobenzene solvate (Form 6) is displayed in Figure 11. Characteristic peaks include 18.4 ⁇ 0.1° 2-Theta, 19.4 ⁇ 0.1° 2-Theta, 20.2 ⁇ 0.1° 2-Theta, 20.9 ⁇ 0.1° 2-Theta, 21.2 ⁇ 0.1° 2-Theta, 21.9 ⁇ 0.1° 2-Theta, and 25.0 ⁇ 0.1° 2- Theta.
  • the X-ray powder diffraction for Compound 1 chlorobenzene solvate has the peaks in Table 6:
  • Angle 2-Theta 0 Intensity % Angle 2-Theta 0 Intensity %
  • the X-ray powder diffraction for Compound 1 acetophenone solvate (Form 7) is displayed in Figure 13. Characteristic peaks include 6.5 ⁇ 0.1° 2-Theta, 13.0 ⁇ 0.1° 2-Theta, 17.6 ⁇ 0.1° 2-Theta, 18.4 ⁇ 0.1° 2-Theta, 19.9 ⁇ 0.1° 2-Theta, 21.0 ⁇ 0.1° 2-Theta, 21.5 ⁇ 0.1° 2-Theta, 22.1 ⁇ 0.1° 2-Theta, and 23.9 ⁇ 0.1° 2-Theta.
  • the X-ray powder diffraction for Compound 1 acetophenone solvate has the peaks in Table 7:
  • Example 13 Single Crystal X-Ray Diffraction of Compound 1 Acetophenone Solvate (Form 5)
  • Weighting scheme w 1 / [ ⁇ 2 (F 0 2 )+( 0.0716P) 2 +0.3711P]
  • Compound 1 acetophenone solvate (Form 5) was characterized by unit cell parameters approximately equal to the following at a temperature of approximately 100(2) K:

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  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

Sont décrits ici des solvates de l'inhibiteur de la tyrosine kinase de Bruton (Btk) l-(R)-3-(4-amino-3-(4-phénoxyphényl)-lH-pyrazolo[3,4-d]pyrimidin-1-yl)pipéridin-1-yl)prop-2-én-1-one, y compris des formes cristallines, et des sels pharmaceutiquement acceptables de ceux-ci. Sont également divulguées des compositions pharmaceutiques contenant les solvates, ainsi que des méthodes d'utilisation de ces solvates, seuls ou combinés à d'autres agents thérapeutiques, pour traiter des maladies ou affections auto-immunes, des maladies ou affections hétéroimmunes, le cancer, dont le lymphome, et des maladies ou affections inflammatoires.
PCT/US2016/024305 2015-03-27 2016-03-25 Formes solvatées d'un inhibiteur de la tyrosine kinase de bruton WO2016160598A1 (fr)

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EP16773859.0A EP3273961A4 (fr) 2015-03-27 2016-03-25 Formes solvatées d'un inhibiteur de la tyrosine kinase de bruton
BR112017020744A BR112017020744A2 (pt) 2015-03-27 2016-03-25 formas solvadas de um inibidor de tirosina quinase de bruton.
JP2017550541A JP2018509457A (ja) 2015-03-27 2016-03-25 ブルトン型チロシンキナーゼ阻害剤の溶媒和形態
CA2981048A CA2981048A1 (fr) 2015-03-27 2016-03-25 Formes solvatees d'un inhibiteur de la tyrosine kinase de bruton
MX2017012430A MX2017012430A (es) 2015-03-27 2016-03-25 Formas solvatadas de un inhibidor de tirosina quinasa de bruton.
AU2016243116A AU2016243116A1 (en) 2015-03-27 2016-03-25 Solvated forms of a Bruton's tyrosine kinase inhibitor
US15/561,615 US20180072738A1 (en) 2015-03-27 2016-03-25 Solvated forms of a bruton's tyrosine kinase inhibitor
CN201680026436.5A CN107530346A (zh) 2015-03-27 2016-03-25 布鲁顿氏酪氨酸激酶抑制剂的溶剂化形式
HK18107889.9A HK1248147A1 (zh) 2015-03-27 2018-06-19 布魯頓氏酪氨酸激酶抑制劑的溶劑化形式
HK18109251.5A HK1249737A1 (zh) 2015-03-27 2018-07-17 布魯頓氏酪氨酸激酶抑制劑的溶劑化形式
US16/224,565 US20190367519A1 (en) 2015-03-27 2018-12-18 Solvated forms of a bruton's tyrosine kinase inhibitor
US16/697,865 US20200347063A1 (en) 2015-03-27 2019-11-27 Solvated forms of a bruton?s tyrosine kinase inhibitor
US17/318,148 US20220106317A1 (en) 2015-03-27 2021-05-12 Solvated forms of a bruton's tyrosine kinase inhibitor
JP2021187233A JP2022033783A (ja) 2015-03-27 2021-11-17 ブルトン型チロシンキナーゼ阻害剤の溶媒和形態

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US10010507B1 (en) 2015-03-03 2018-07-03 Pharmacyclics Llc Pharmaceutical formulations of a bruton's tyrosine kinase inhibitor
US10065968B2 (en) 2012-06-04 2018-09-04 Pharmacyclics Llc Crystalline forms of a bruton's tyrosine kinase inhibitor
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US10183024B2 (en) 2016-12-02 2019-01-22 Apotex Inc. Crystalline forms of ibrutinib
EP3501609A1 (fr) 2017-12-08 2019-06-26 Zentiva K.S. Compositions pharmaceutiques comprenant de l'ibrutinib
EP3575300A1 (fr) 2018-05-31 2019-12-04 Apotex Inc. Nouvelles formes cristallines d'ibrutinib
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US10752634B2 (en) 2012-06-04 2020-08-25 Pharmacyclics Llc Crystalline forms of a brutons tyrosine kinase inhibitor
US10065968B2 (en) 2012-06-04 2018-09-04 Pharmacyclics Llc Crystalline forms of a bruton's tyrosine kinase inhibitor
US10106548B2 (en) 2012-06-04 2018-10-23 Pharmacyclics Llc Crystalline forms of a Bruton's tyrosine kinase inhibitor
US10125140B1 (en) 2012-06-04 2018-11-13 Pharmacyclics Llc Crystalline forms of a bruton's tyrosine kinase inhibitor
US10961251B1 (en) 2012-06-04 2021-03-30 Pharmacyclics Llc Crystalline forms of a Bruton's tyrosine kinase inhibitor
US10266540B2 (en) 2012-06-04 2019-04-23 Pharmacyclics Llc Crystalline forms of a Bruton's tyrosine kinase inhibitor
US10294231B2 (en) 2012-06-04 2019-05-21 Pharmacyclics Llc Crystalline forms of a Bruton's tyrosine kinase inhibitor
US10294232B2 (en) 2012-06-04 2019-05-21 Pharmacyclics Llc Crystalline forms of a Bruton's tyrosine kinase inhibitor
US10010507B1 (en) 2015-03-03 2018-07-03 Pharmacyclics Llc Pharmaceutical formulations of a bruton's tyrosine kinase inhibitor
US10828259B2 (en) 2015-03-03 2020-11-10 Pharmacyclics Llc Pharmaceutical formulations of a Bruton's tyrosine kinase inhibitor
US10213386B2 (en) 2015-03-03 2019-02-26 Pharmacyclics Llc Pharmaceutical formulations of a Bruton's tyrosine kinase inhibitor
EP3337485A4 (fr) * 2015-08-19 2019-01-09 Sun Pharmaceutical Industries Ltd Formes cristallines d'ibrutinib
US11001585B2 (en) 2015-08-19 2021-05-11 Sun Pharmaceutical Industries Limited Crystalline forms of ibrutinib
EP3243824A1 (fr) * 2016-05-11 2017-11-15 Zentiva K.S. Les formes solides de la base libre de l'ibrutinib
US10183024B2 (en) 2016-12-02 2019-01-22 Apotex Inc. Crystalline forms of ibrutinib
EP3501609A1 (fr) 2017-12-08 2019-06-26 Zentiva K.S. Compositions pharmaceutiques comprenant de l'ibrutinib
EP3575300A1 (fr) 2018-05-31 2019-12-04 Apotex Inc. Nouvelles formes cristallines d'ibrutinib
US10688050B1 (en) 2018-12-21 2020-06-23 Synthon B.V. Pharmaceutical composition comprising ibrutinib
EP3669867A1 (fr) 2018-12-21 2020-06-24 Synthon B.V. Composition pharmaceutique comprenant de l'ibrutinib
WO2020127912A1 (fr) 2018-12-21 2020-06-25 Synthon B.V. Composition pharmaceutique comprenant de l'ibrutinib
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US20180072738A1 (en) 2018-03-15
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